(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
(19) World Intellectual Property Organization /
Internationa] Bureau
^ i iiiii iiiiiiii ii mill urn inn mil mi 1 11 m urn urn mil mil urn mi limn mi mi mi
(43) International Publication Date
13 April 2006 (13.04.2006)
PCT
(10) International Publication Number
WO 2006/038923 A2
(51) International Patent Classification:
A61K 31/4745 (2006.01) C07D 471/02 (2006.01)
(22)
International Filing Date:
17 June 2005 (17.06.2005)
(25)
Filing Language:
English
(26)
Publication Language:
English
(30)
Priority Data:
60/581,317
8 June 2004 (18.06 .2004 ) US
(71) Applicant (for all designated States except US): 3M
INNOVATIVE PROPERTIES COMPANY [US/US];
j 3M Center, Post Office Box 33427, Saint Paul, Minnesota
| 55133-3427 (US).
j (72) Inventors; and
j (75) Inventors/Applicants (for US only): NIWAS, Shri
! [US/US]; 3M Center, Post Office Box 33427, Saint Paul,
| Minnesota 55133-3427 (US). MERRILL, Bryon, A.
j [US/US]; 3M Center, Post Office Box 33427, Saint Paul,
j Minnesota 55133-3427 (US). HEPPNER, Philip, D.
! [US/US]; 3M Center, Post Office Box 33427, Saint Paul,
j Minnesota 55133-3427 (US). KSHIRSAGAR, Tushar,
j A. [IN/US]; 3M Center, Post Office Box 33427, Saint Paul,
j Minnesota 55133-3427 (US). LUNDQUIST, Gregory,
I D., Jr. [US/US] ; 3M Center, Post Office Box 33427, Saint
j Paul, Minnesota 55133-3427 (US). AMOS, David, T.
| [US/US]; 3M Center, Post Office Box 33427, Saint Paul,
! Minnesota 55133-3427 (US). LINDSTROM, Kyle, J.
j [US/US]; 3M Center, Post Office Box 33427, Saint Paul,
j Minnesota 55133-3427 (US).
(74) Agents: ERSFELD, Dean, A. et al.; Office Of Intellec-
tual Property Counsel, Post Office Box 33427, Saint Paul,
Minnesota 55133-3427 (US).
(81) Designated States (unless otherwise indicated, for every
kind of national protection available): AE, AG, AL, AM,
AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI,
GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE,
KG, KM, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA,
MD, MG, MK, MN, MW, MX, MZ, NA, NG, NI, NO, NZ,
OM, PG, PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL,
SM, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC,
VN, YU, ZA, ZM, ZW.
(84) Designated States (unless otherwise indicated, for every
kind of regional protection available): ARIPO (BW, GH,
GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI,
FR, GB, GR, HU, IE, IS, IT, LT, LU, MC, NL, PL, PT, RO,
SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN,
GQ, GW, ML, MR, NE, SN, TD, TG).
er Rule 4.17:
— as to applit ant V entitlement to apply for and be granted a
patent (Rule 4.17(H))
— as in the applicant V ent itlement to claim the priority of the
earlier application (Rule 4. 17 (Hi))
Published:
— without international search report and to be republished
upon receipt of that report
For two-letter codes and other abbreviations, refer to the "Guid-
ance Notes on Codes and Abbreviations" appearing at the begin-
ning of each regular issue of the PCT Gazette.
(54) Title: ARYL SUBSTITUTED IMIDAZONAPHTHYRIDINES
^= (57) Abstract: Imidazonaphthyridine ring systems substituted with an aryl substituent, pharmaceutical compositions containing the
^= compounds, and methods of use of these compounds as immunomodulators, for inducing cytokine biosynthesis in animals and in
the treatment of diseases including viral and neoplastic diseases are disclosed.
fN
fN
o\
00
m
o
o
o
fN
o
WO 2006/038923
PCT7US2005/021436
ARYL SUBSTITUTED IMEDAZONAPHTHYRIDINES
5 CROSS-REFERENCE TO RELATED APPLICATIONS
The present application claims priority to U.S. Provisional Application Serial No.
60/581317, filed on June 18, 2004, which is incorporated herein by reference in its
entirety.
10 BACKGROUND
In the 1950's the lH-imidazo[4,5-c]quinoline ring system was developed and l-(6-
methoxy-8-quinolinyl)-2-methyl-l J 9 r -imidazo[4,5-c]quinoline was synthesized for possible
use as an antimalarial agent. Subsequently, syntheses of various substituted \H-
imidazo[4,5-c]quinolines were reported. For example, l-[2-(4-piperidyl)ethyl]-lfl r -
15 imidazo[4,5-c]quinoline was synthesized as a possible anticonvulsant and cardiovascular
agent. Also, several 2-oxoimidazo[4,5-c]quinolines have been reported.
Certain li?-imidazo[4,5-c]quinolin-4-amines and 1- and 2-substituted derivatives
thereof were later found to be useful as antiviral agents, bronchodilators and
immunomodulators. Subsequently, certain substituted l#-imidazo[4,5-c]pyridin-4-amine,
20 quinolin-4-amine, tetrahydroquinolm-4-amine, naphthyridin-4-amine, and
tetrahydronaphthyridin-4-amine compounds as well as certain analogous thiazolo and
oxazolo compounds were synthesized and found to be useful as immune response
modifiers, rendering them useful in the treatment of a variety of disorders.
There continues to be interest in the imidazoquinoline ring system, as well as other
25 imidazo ring systems, and there is a continuing need for compounds that have the ability
to modulate the immune response, by induction of cytokine biosynthesis or other
mechanisms.
1
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SUMMARY
The present invention provides anew class of compounds that are useful in
inducing cytokine biosynthesis in animals. Such compounds are of the following Formula
(I):
wherein R A , Rb, Ri, and R 2 , are as defined below.
1 0 The compounds of Formula I include various isomers of aryl substituted
imidazonaphthyridines, in particular 1,5-naphthyridines, which are preferably substituted
at the 7 position.
The compounds of Formula I are useful as immune response modifiers due to their
ability to induce cytokine biosynthesis (e.g., induce the synthesis of at least one cytokine)
1 5 and otherwise modulate the immune response when administered to animals (e.g., by
inhibiting the induction of TNF-alpha). This makes the compounds useful in the treatment
of a variety of conditions such as viral diseases and tumors that are responsive to such
changes in the immune response.
The invention further provides pharmaceutical compositions containing an
20 effective amount of a compound of Formula I, and methods of inducing cytokine
biosynthesis in an animal, treating a viral infection and/or treating a neoplastic disease in
an animal by administering an effective amount of a compound of Formula I to the animal.
hi addition, methods of synthesizing compounds of Formula I and intermediates
useful in the synthesis of these compounds are provided.
25 As used herein, "a," "an," "the," "at least one," and "one or more" are used
interchangeably.
The terms "comprises" and variations thereof do not have a limiting meaning
where these terms appear in the description and claims.
The above summary of the present invention is not intended to describe each
2
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disclosed embodiment or every implementation of the present invention. The description
that follows more particularly exemplifies illustrative embodiments, fn several places
throughout the application, guidance is provided through lists of examples, which
examples can be used in various combinations. In each instance, the recited list serves
5 only as a representative group and should not be interpreted as an exclusive list.
DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
OF THE INVENTION
The present invention provides compounds of the following Formula (I):
10
as well as more specific compounds of the following Formulas (II, III, IV, V, VI, and VII):
20
3
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wherein R A , Rb, R, Ri, R2, R3, G, and n are as defined below, and pharmaceutically
acceptable salts thereof.
WO 2006/038923
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In one embodiment, there is provided a compound of the Formula (I):
NH 2
r b T i
R A R 1
wherein:
R A and R B join to form a fused pyridine ring which is substituted by one R 3 group
or substituted by one R 3 group and one R group;
Ri is selected from the group consisting of:
-R4,
-X-R4,
-X-Y-R4,
-X-Y-X-Y-R4, and
-X-R 5 ;
R 2 is selected from the group consisting of:
-R4,
-X-R4,
-X-Y-R4, and
-X-R 5 ;
R 3 is selected from the group consisting of:
-Z-Ar,
-Z-Ar'-Y-Rt,
-Z-Ar'-X-Y-R4,
-Z-Ar'-R 5 , and
-Z-Ar*-X-R 5 ;
R is selected from the group consisting of alkyl, alkoxy, chloro, fluoro, hydroxy,
and trifluoromethyl;
Ar is selected from the group consisting of aryl and heteroaryl both of which can
be unsubstituted or can be substituted by one or more substituents independently selected
from the group consisting of alkyl, alkenyl, alkoxy, methylenedioxy, haloalkyl,
haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano, carboxy, formyl,
5
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aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,
heterocyclyl, heterocyclylalkylenyl, alkoxyalkylenyl, a-aminocarboxyalkylenyl, amino,
aminoalkyl, alkylamino, and dialkylamino;
Ar' is selected from the group consisting of arylene and heteroarylene both of
which can be unsubstituted or can be substituted by one or more substituents
independently selected from the group consisting of alkyl, alkenyl, alkoxy, haloalkyl,
haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano, carboxy, formyl,
aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,
heterocyclyl, heterocyclylalkylenyl, amino, alkylamino, and dialkylamino;
X is selected from the group consisting of alkylene, alkenylene, alkynylene,
arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and
alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene,
or heterocyclylene, and optionally interrupted by one or more -O- groups;
Y is selected from the group consisting of:
-S(O) 0 -2-,
-S(0) 2 -N(R 8 )-,
-C(R 6 )-,
-C(R 6 )-0-,
-0-C(R 6 )-,
-0-C(0)-0-,
-N(R 8 )-Q-,
-C(R6)-N(R 8 )-,
-0-C(R 6 )-N(R 8 )-,
-C(R 6 )-N(OR 9 )-,
,N-Q —
WO 2006/038923
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-N-C(R 6 )-N-W-
-N— R-N-Q-
-V-N
, and
N-C(R 6 )-N
Z is selected from the group consisting of a bond, alkylene, alkenylene, and
alkynylene;
R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,
arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,
heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,
alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl,
heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups
can be unsubstituted or substituted by one or more substituents independently selected
from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen,
nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy,
heteroarylalkyleneoxy, heterocyclyl, amino, carboxy, alkylamino, dialkylamino,
(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl,
oxo;
R 5 is selected from the group consisting of:
/-(CH^-. ^ ^(CH 2 ) a -^
-N-C(R 6 ) -N-S(0) 2 _ V -t4 I -f N-C(R 6 )-N A
V , V , W-^and W
R 6 is selected from the group consisting of =0 and =S;
R7 is C2-7 alkylene;
R 8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and
arylalkylenyl;
R 9 is selected from the group consisting of hydrogen and alkyl;
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Rio is C3-8 alkylene;
Rn is selected from the group consisting of fiuoro, hydroxy, and alkoxy;
A is selected from the group consisting of -0-, -C(O)-, -S(O) 0 -2-, -CH 2 -, and
-NOEU)-;
Q is selected from the group consisting of a bond, -C(Re)-, -C(R6)-C(R 6 ), -S(0) 2 -,
-C(R6)-N(R 8 )-W-, -S(0) 2 -N(R 8 )-, -C(R 6 )-0-, and -C(R6)-N(OR 9 )-;
V is selected from the group consisting of -C(R6>, -0-C(R 6 )-, -N(R 8 )-C(R 6 )-, and
-S(0) 2 -;
W is selected from the group consisting of a bond, -C(O)-, and-S(0) 2 -; and
a and b are independently integers from 1 to 6 with the proviso that a + b is < 7;
or a pharmaceutically acceptable salt thereof.
hi one embodiment, there is provided a compound of the Formula (I):
R A and R B join to form a fused pyridine ring which is substituted by one R 3 group
or substituted by one R 3 group and one R group;
Ri is selected from the group consisting of:
-R4,
-X-R4,
-X-Y-R4,
-X-Y-X-Y-R4, and
-X-R 5 ;
R 2 is selected from the group consisting of:
-R4,
-X-R4,
-X-Y-R4, and
R A R 1
I
wherein:
WO 2006/038923
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R 3 is selected from the group consisting of:
-Z-Ar,
-Z-Ar'-Y-IU,
5 -Z-Ar'-X-Y-R4,
-Z-Ar*-R 5 , and
-Z-Ar'-X-Rs;
R is selected from the group consisting of alkyl, alkoxy, chloro, fluoro, hydroxy,
and trifluoromethyl;
10 Ar is selected from the group consisting of aryl and heteroaryl both of which can
be unsubstituted or can be substituted by one or more substituents independently selected
from the group consisting of alkyl, alkenyl, alkoxy, methylenedioxy, haloalkyl,
haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano, carboxy, formyl,
aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,
15 heterocyclyl, heterocyclylalkylenyl, amino, aminoalkyl, alkylamino, and dialkylamino;
Ar' is selected from the group consisting of arylene and heteroarylene both of
which can be unsubstituted or can be substituted by one or more substituents
independently selected from the group consisting of alkyl, alkenyl, alkoxy, haloalkyl,
haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano, carboxy, formyl,
20 aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,
heterocyclyl, heterocyclylalkylenyl, amino, alkylamino, and dialkylamino;
X is selected from the group consisting of alkylene, alkenylene, alkynylene,
arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and
alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene,
25 or heterocyclylene, and optionally interrupted by one or more -O- groups;
Y is selected from the group consisting of:
-S(0)o- 2 -,
-S(0) 2 -N(Rs)-,
-C(R 6 )-,
30 -C(R 6 )-0-,
-0-C(R 6 )-,
-0-C(0)-0-,
9
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-N(R 8 )-Q-,
-C(R 6 )-N(R 8 )-,
-0-C(R 6 )-N(R 8 )-,
-C(R 6 )-N(OR 9 )-,
N-Q-
J
-N-C(Re)-N-W-
-N— R-N-Q-
^ rX
-V-N
N-C(R,)-IS
Z is selected from the group consisting of a bond, alkylene, alkenylene, and
alkynylene;
R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,
arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,
heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,
alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl,
heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups
can be unsubstituted or substituted by one or more substituents independently selected
from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen,
nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy,
heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino,
(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl,
oxo;
R 5 is selected from the group consisting of:
10
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^(CH 2 ) a . ^ r (CH2)a ^
-N-C(Re) -N-S(0) 2 _ V -^j \ 4- N-C(R 6 )-N A
V , V , W^, and W
R 6 is selected from the group consisting of =0 and =S;
R 7 is C2-7 akylene;
R 8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and
arylalkylenyl;
R 9 is selected from the group consisting of hydrogen and alkyl;
Rio is C3-8 alkyl ene;
A is selected from the group consisting of -0-, -C(O)-, -S(0)o-2-, -CH 2 -, and
-N(R4)-;
Q is selected from the group consisting of a bond, -C(R 6 )-, -C(R 6 )-C(R6), -S(0) 2 -,
-C(R 6 )-N(R 8 )-W-, -S(0) 2 -N(R 8 )-, -C(R 6 )-0-, and -C(R6)-N(OR 9 )-;
V is selected from the group consisting of -C(R 6 )-, -0-C(R 6 )-, -N(Rg)-C(R 6 )-, and
-S(0) r ;
W is selected from the group consisting of a bond, -C(O)-, and -S(0>2-; and
a and b are independently integers from 1 to 6 with the proviso that a + b is < 7;
or a pharmaceutically acceptable salt thereof.
In another embodiment, there is provided a compound of the Formula (II):
wherein:
n is 0 or 1;
Ri is selected from the group consisting of:
-R4,
-X-R4,
-X-Y-R4,
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-X-Y-X-Y-R4, and
-X-R 5 ;
R 2 is selected from the group consisting of:
-R4,
5 -X-R4,
-X-Y-R4, and
-X-R 5 ;
R 3 is selected from the group consisting of:
-Z-Ar,
10 -Z-Ar'-Y-R4,
-Z-Ar'-X-Y-R4,
-Z-Ar'-R 5 , and
-Z-Ar'-X-R 5 ;
R is selected from the group consisting of alkyl, alkoxy, chloro, fluoro, hydroxy,
15 and trifluoromethyl;
Ar is selected from the group consisting of aryl and heteroaryl both of which can
be unsubstituted or can be substituted by one or more substituents independently selected
from the group consisting of alkyl, alkenyl, alkoxy, methylenedioxy, haloalkyl,
haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano, carboxy, formyl,
20 aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,
heterocyclyl, heterocyclylalkylenyl, amino, aminoalkyl, alkylamino, and dialkylamino;
Ar' is selected from the group consisting of arylene and heteroarylene both of
which can be unsubstituted or can be substituted by one or more substituents
independently selected from the group consisting of alkyl, alkenyl, alkoxy, haloalkyl,
25 haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano, carboxy, formyl,
aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,
heterocyclyl, heterocyclylalkylenyl, amino, alkylamino, and dialkylamino;
X is selected from the group consisting of alkylene, alkenylene, alkynylene,
arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and
30 alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene,
or heterocyclylene, and optionally interrupted by one or more -O- groups;
Y is selected from the group consisting of:
12
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-S(O) 0 -2-,
-S(0) 2 -N(R 8 )-,
-C(R 6 )-,
-C(R 6 )-0-,
-0-C(R 6 )-,
-0-C(0)-0- 5
-N(R 8 )-Q-,
-C(R 6 )-N(R 8 )-,
-0-C(R 6 )-N(R 8 )-,
-C(R6)-N(OR 9 )-,
Z is selected from the group consisting of a bond, alkylene, alkenylene, and
alkynylene;
R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,
arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,
heteroaryloxyalkylenyl, alkylheteroarylenyl, andheterocyclyl wherein the alkyl, alkenyl,
alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl,
heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups
can be unsubstituted or substituted by one or more substituents independently selected
from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen,
-N-C(R 6 )-N-W-
— N — R 7 -N-Q-
—V-N
13
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nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy,
heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino,
(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl,
oxo ;
R 5 is selected from the group consisting of:
^(CH 2 ) a . / ^ ^(CH 2 ) a ^
-N-C(R 6 ) -N-S(0) 2 \ -f- N-C(R 6 )-N A
V , V , W^ and W W ^;
R6 is selected from the group consisting of =0 and =S;
R 7 is C2-7 alkylene;
R 8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and
arylalkylenyl;
R 9 is selected from the group consisting of hydrogen and alkyl;
Rio is C3-8 alkylene;
A is selected from the group consisting of -0-, -C(O)-, -S(O) 0 -2-, -CH 2 -, and
-N(R4)-;
Q is selected from the group consisting of a bond, -C(R 6 )-, -C(R S >C(R 6 ), -S(0) 2 -,
-C(R 6 )-N(R 8 )-W-, -S(0) 2 -N(R 8 )-, -C(R 6 )-0-, and -C(R 6 )-N(OR 9 )-;
V is selected from the group consisting of -C(R 6 )-, -0-C(R 6 )-, -N"(R 8 )-C(R 6 )-, and
-S(0) 2 -;
W is selected from the group consisting of a bond, -C(O)-, and -S(0) 2 -; and
a and b are independently integers from 1 to 6 with the proviso triat a + b is < 7;
or a pharmaceutically acceptable salt thereof.
hi another embodiment, there is provided a compound of the Formula (III):
14
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wherein:
Ri is selected from the group consisting of:
-R4,
-X-R4,
-X-Y-R4,
-X-Y-X-Y-R4, and
-X-R 5 ;
R 2 is selected from the group consisting of:
-R4,
-X-R4,
-X-Y-R4, and
-X-R 5 ;
R 3 is selected from the group consisting of:
-Z-Ar,
-Z-Ar*-Y-R4,
-Z-Ar'-X-Y-R4,
-Z-Ar'-R 5 , and
-Z-Ar'-X-R 5 ;
Ar is selected from the group consisting of aryl and heteroaryl both of which can
be unsubstituted or can be substituted by one or more substituents independently selected
from the group consisting of alkyl, alkenyl, alkoxy, methylenedioxy, haloalkyl,
haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano, carboxy, formyl,
aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,
heterocyclyl, heterocyclylalkylenyl, amino, aminoalkyl, alkylamino, and dialkylamino;
Ar' is selected from the group consisting of arylene and heteroarylene both of
which can be unsubstituted or can be substituted by one or more substituents
independently selected from the group consisting of alkyl, alkenyl, alkoxy, haloalkyl,
haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano, carboxy, formyl,
aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,
heterocyclyl, heterocyclylalkylenyl, amino, alkylamino, and dialkylamino;
X is selected from the group consisting of alkylene, alkenylene, alkynylene,
arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and
15
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alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene,
or heterocyclylene, and optionally interrupted by one or more -O- groups;
Y is selected from the group consisting of:
-S(0)o- 2 -,
-S(0) 2 -N(R 8 )-,
-C(R 6 )-,
-C(R 6 )-0-,
-0-C(R 6 )-,
-0-C(0)-0-,
-N(R 8 )-Q-,
-C(R 6 )-N(R 8 )-,
-0-C(R 6 )-N(R 8 )-,
-C(R 6 )-N(OR 9 )-,
J- N-Q —
Z is selected firom the group consisting of a bond, alkylene, alkenylene, and
alkynylene;
R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,
arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,
heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,
alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl,
-N-C(R 6 )-N-W~
-N- R 7 "N-Q-
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heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups
can be unsubstituted or substituted by one or more substituents independently selected
from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen,
nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy,
5 heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino,
(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl,
oxo ;
R 5 is selected from the group consisting of:
WCH 2 ) a . / ^ ^(CH 2 ) a ^
-N-C(R 6 ) -N-S(0) 2 _v-|<l \ "f N-C(R 6 )-N A
10 R.6 is selected from the group consisting of =0 and =S;
R 7 is C2-7 alkylene;
R 8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and
arylalkylenyl;
R 9 is selected from the group consisting of hydrogen and alkyl;
15 Rio is C3-8 alkylene;
A is selected from the group consisting of -0-, -C(O)-, -S(0)o-2-, -CH 2 -, and
-N(R4)-;
Q is selected from the group consisting of a bond, -C(Re)-, -C(R6)-C(Re), -S(0)2-,
-C(R 6 )-N(R 8 )-W-, -S(0) 2 -N(R 8 )-, -C^-O-, and -C(R 6 )-N(OR 9 )-;
20 V is selected from the group consisting of -CXRe)-, -0-C(R6)-, -N(R 8 )-C(R6)-, and
-S(0) 2 -;
W is selected from the group consisting of a bond, -C(O)-, and -S(0) 2 -; and
a and b are independently integers from 1 to 6 with the proviso that a + b is < 7;
or a pharmaceutically acceptable salt thereof.
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In another embodiment, the present invention provides a compound of the Formula
(IV):
5 IV
wherein:
n is 0 or 1 ;
Ri is selected from the group consisting of:
-R4,
10 -X-R4,
-X-Y-R4,
-X-Y-X-Y-R4, and
-X-R 5 ;
R2 is selected from the group consisting of:
15 -R4,
-X-R4,
-X-Y-R4, and
-X-R 5 ;
R 3 is selected from the group consisting of:
20 -Z-Ar,
-Z-Ar'-Y-R),
-Z-Ar'-X-Y-R4,
-Z-Ar'-R 5 , and
-Z-Ar'-X-R 5 ;
25 R is selected from the group consisting of alkyl, alkoxy, chloro, fluoro, hydroxy,
and trifluoromethyl;
Ar is selected from the group consisting of aryl and heteroaryl both of which can
be unsubstituted or can be substituted by one or more substituents independently selected
from the group consisting of alkyl, alkenyl, alkoxy, methylenedioxy, haloalkyl,
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haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano, carboxy, formyl,
aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,
heterocyclyl, heterocyclylalkylenyl, amino, aminoalkyl, alkylamino, and dialkylamino;
Ar' is selected from the group consisting of arylene and heteroarylene both of
which can be unsubstituted or can be substituted by one or more substituents
independently selected from the group consisting of alkyl, alkenyl, alkoxy, haloalkyl,
haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano, carboxy, formyl,
aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,
heterocyclyl, heterocyclylalkylenyl, amino, alkylamino, and dialkylamino;
X is selected from the group consisting of alkylene, alkenylene, alkynylene,
arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and
alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene,
or heterocyclylene, and optionally interrupted by one or more -O- groups;
Y is selected from the group consisting of:
-S(O) 0 -2-,
-S(0) 2 -N(R 8 )-,
-C(R 6 )-,
-C(R 6 )-0-,
-0-C(R6)-,
-0-C(0)-0-,
-N(R 8 )-Q-,
-C(R 6 )-N(R 8 )-,
-0-C(R 6 )-N(R 8 )-,
-C(R6)-N(OR 9 )-,
-L N-Q —
-N-C(R 6 )-N-W-
— N — R 7 -N-Q-
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Z is selected from the group consisting of a bond, alkylene, alkenylene, and
alkynylene;
R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,
arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,
heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,
alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl,
heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups
can be unsubstituted or substituted by one or more substituents independently selected
from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen,
nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy,
heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino,
(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl,
oxo;
R 5 is selected from the group consisting of:
WCH 2 ) a . ^(CH 2 ) a -^
-N-C(R 6 ) -N-S(0) 2 — V -|4 \ "f N-C(R 6 )-N A
R6 is selected from the group consisting of =0 and =S;
R 7 is C2-7 alkylene;
R 8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and
arylalkylenyl;
R9 is selected from the group consisting of hydrogen and alkyl;
Rio is C3.8 alkylene;
A is selected from the group consisting of -0-, -C(O)-, -S(O) 0 -2-, -CH 2 -, and
-NCR4)-;
Q is selected from the group consisting of a bond, -C(Re)-, -C(R6)-C(R6), -S(0) 2 -,
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-C(R 6 )-N(R 8 )-W-, -S(0) 2 -N(R 8 )-, -C(R6)-0-, and -C(R6)-N(OR 9 )-;
V is selected from the group consisting of -C(R 6 )-, -0-C(R 6 )-, -N(R 8 )-C(R 6 )-, and
-S(0) 2 -;
W is selected from the group consisting of a bond, -C(O)-, and -S(0) 2 -; and
a and b are independently integers from 1 to 6 with the proviso that a + b is < 7;
or a pharmaceutically acceptable salt thereof.
In another embodiment, there is provided a compound of the Formula (V):
n is 0 or 1 ;
Ri is selected from the group consisting of:
-R4,
-X-R4,
-X-Y-R4,
-X-Y-X-Y-R4, and
-X-R 5 ;
R 2 is selected from the group consisting of:
-R4,
-X-R4,
-X-Y-R4, and
-X-R 5 ;
R3 is selected from the group consisting of:
-Z-Ar,
-Z-Ar'-Y-R4,
-Z-Ar*-X-Y-R4,
-Z-Ar'-R 5 , and
V
wherein:
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-Z-Ar'-X-R 5 ;
R is selected from the group consisting of alkyl, alkoxy, chloro, fluoro, hydroxy,
and trifluoromethyl;
Ar is selected from the group consisting of aryl and heteroaryl both of which can
be unsubstituted or can be substituted by one or more substituents independently selected
from the group consisting of alkyl, alkenyl, alkoxy, methylenedioxy, haloalkyl,
haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano, carboxy, formyl,
aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,
heterocyclyl, heterocyclylalkylenyl, amino, aminoalkyl, alkylamino, and dialkylamino;
Ar' is selected from the group consisting of arylene and heteroarylene both of
which can be unsubstituted or can be substituted by one or more substituents
independently selected from the group consisting of alkyl, alkenyl, alkoxy, haloalkyl,
haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano, carboxy, formyl,
aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,
heterocyclyl, heterocyclylalkylenyl, amino, alkylamino, and dialkylamino;
X is selected from the group consisting of alkylene, alkenylene, alkynylene,
arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and
alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene,
or heterocyclylene, and optionally interrupted by one or more -O- groups;
Y is selected from the group consisting of:
-S(0)o- 2 -,
-S(0) 2 -N(R 8 )-,
-C(R 6 )-,
-C(R 6 )-0-,
-0-C(R 6 )-,
-0-C(0)-O-
-N(R 8 )-Q-,
-C(R 6 )-N(R 8 )-,
-0-C(R 6 )-N(R 8 )-,
-C(R 6 )-N(OR 9 )-,
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N-Q —
— V-N
N-C(Re)-^
5
Z is selected from the group consisting of a bond, alkylene, alkenylene, and
alkynylene;
R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,
arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,
10 heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,
alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl,
heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups
can be unsubstituted or substituted by one or more substituents independently selected
from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen,
15 nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy,
heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino,
(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl,
oxo;
R 5 is selected from the group consisting of:
20
R 6 is selected from the group consisting of =0 and =S;
R 7 is C2-7 alkylene;
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R 8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and
arylalkylenyl;
R 9 is selected from the group consisting of hydrogen and alkyl;
Rio is C 3 -s alkylene;
A is selected from the group consisting of -0-, -C(O)-, -S(O) 0 - 2 -, -CH 2 -, and
-N(R4)-;
Q is selected from the group consisting of a bond, -CQRe)-, -C(R6)-C(Re), -S(0)2-,
-C(R 6 )-N(R 8 )-W-, -S(0) 2 -N(R 8 )-, -C(R 6 )-0-, and -CCR 6 >N(OR 9 )s
V is selected from the group consisting of -C(R 6 >, -0-C(R 6 )-, -N(R 8 )-C(R 6 )-, and
-S(0) 2 -;
W is selected from the group consisting of a bond, -CCO)-, and -S(0) 2 -; and
a and b are independently integers from 1 to 6 with the proviso that a + b is < 7;
or a pharmaceutically acceptable salt thereof.
In another embodiment, there is provided a compound of the Formula (VI):
n is 0 or 1;
Ri is selected from the group consisting of:
-R4,
-X-R4,
-X-Y-R4,
-X-Y-X-Y-R4, and
-X-R 5 ;
R 2 is selected from the group consisting of:
-R4,
-X-R4,
-X-Y-R4, and
VI
wherein:
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-X-R 5 ;
R 3 is selected from the group consisting of:
-Z-Ar,
-Z-Ar'-Y-R4,
-Z-Ar'-X-Y-R4,
-Z-Ar'-R 5 , and
-Z-Ar'-X-R 5 ;
R is selected from the group consisting of alkyl, alkoxy, chloro, fluoro, hydroxy,
and trifluoromethyl;
Ar is selected from the group consisting of aryl and heteroaryl both of which can
be unsubstituted or can be substituted by one or more substituents independently selected
from the group consisting of alkyl, alkenyl, alkoxy, methylenedioxy, haloalkyl,
haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano, carboxy, forrnyl,
aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,
heterocyclyl, heterocyclylalkylenyl, amino, aminoalkyl, alkylamino, and dialkylamino;
Ar' is selected from the group consisting of arylene and heteroarylene both of
which can be unsubstituted or can be substituted by one or more substituents
independently selected from the group consisting of alkyl, alkenyl, alkoxy, haloalkyl,
haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano, carboxy, forrnyl,
aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,
heterocyclyl, heterocyclylalkylenyl, amino, alkylamino, and dialkylamino;
X is selected from the group consisting of alkylene, alkenylene, alkynylene,
arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and
alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene,
or heterocyclylene, and optionally interrupted by one or more -O- groups;
Y is selected from the group consisting of:
-S(0)o- 2 -,
-S(0) 2 -N(R 8 )-,
-c(R 6 y,
-C(R 6 )-0-,
-0-C(R 6 )-,
-0-C(0)-0-,
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-N(R 8 )-Q-,
-C(R 6 )-N(R 8 )-,
-0-C(R 6 )-N(R 8 )-,
-C(R 6 )-N(OR 9 )-,
Z is selected from the group consisting of a bond, alkylene, alkenylene, and
alkynylene;
R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,
arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,
heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,
alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl,
heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups
can be unsubstituted or substituted by one or more substituents independently selected
from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen,
nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy,
heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino,
(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl,
oxo;
R 5 is selected from the group consisting of:
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-N-C(R 6 ) -N-S(0) 2 _v-Kl \ 4- N-C(R 6 )-N A
t R J R ^ \, CH > J ^ rJ
R 6 is selected from the group consisting of =0 and =S;
R 7 is C2-7 alkylene;
R 8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and
arylalkylenyl;
R 9 is selected from the group consisting of hydrogen and alkyl;
Rio is C 3 -s alkylene;
A is selected from the group consisting of -0-, -C(O)-, -S(O) 0 -2-, -CH 2 -, and
-N(R4)-;
Q is selected from the group consisting of a bond, -C(Re)-, -C(R6)-C(R6), -S(0)2-,
-C(R 6 )-N(R 8 )-W-, -S(0) 2 -N(R 8 )-, -C(R 6 )-0-, and -C(R6)-N(OR 9 )-;
V is selected from the group consisting of -C(R 6 )-, -0-C(R 6 )-, -N(R 8 )-C(R 6 )-, and
-S(0) 2 -;
W is selected from the group consisting of a bond, -C(O)-, and -S(0) 2 -; and
a and b are independently integers from 1 to 6 with the proviso that a + b is < 7;
or a pharmaceutically acceptable salt thereof.
For certain embodiments, the present invention provides a compound (which is a
prodrug) of the Formula (VII):
vn
wherein:
G is selected from the group consisting of:
-C(0)-R',
a-aminoacyl,
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a-aminoacyl-a-aminoacyl,
-C(0)-0-R',
-C(0)-N(R")R\
-C(=NY')-R',
5 -CH(OH)-C(0)-OY',
-CH(OCi. 4 alkyl)Y 0 ,
-CH 2 Yi, and
-CH(CH 3 )Y i;
R' and R" are independently selected from the group consisting of C1-10 alkyl,
10 C3.7 cycloalkyl, and benzyl, each of which may be unsubstituted or substituted by one or
more substitutents selected from the group consisting of halogen, hydroxy, nitro, cyano,
carboxy, C1-6 alkyl, Ci_ 4 alkoxy, aryl, heteroaryl, arylCi-4 alkylenyl,
heteroarylCi.4 alkylenyl, halod.4 alkylenyl, haloCi-4 alkoxy, -0-C(0)-CH 3 , -C(0)-0-CH 3 ,
-C(0)-NH 2 , -0-CH 2 -C(0)-NH 2 , -NH 2 , and -S(0) 2 -NH 2 , with the proviso that R" can also
15 be hydrogen;
a-aminoacyl is an acyl group derived from an amino acid selected from the group
consisting of racemic, D-, and L-amino acids;
Y' is selected from the group consisting of hydrogen, C1-6 alkyl, and benzyl;
Y 0 is selected from the group consisting of Ci_ 6 alkyl, carboxyCi-6 alkylenyl,
20 aminoCi-4 alkylenyl, mono-iV-Ci-6 alkylaminoCi-4 alkylenyl, and
di-N,N-C\-6 alkylaminoCi-4 alkylenyl;
Yi is selected from the group consisting of mono-7V-Ci-6 alkylamino,
di-A^iV-Ci-6 alkylamino, morpholin-4-yl, piperidin-l-yl, pyrrolidin-l-yl, and
4-C1.4 alkylpiperazin-l-yl;
25 Ri is selected from the group consisting of:
-R4,
-X-R4,
-X-Y-Rt,
-X-Y-X-Y-R4, and
30 -X-R 5 ;
R 2 is selected from the group consisting of:
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-X-R4,
-X-Y-R4, and
-X-R 5 ;
R 3 is selected from the gi-oup consisting of:
-Z-Ar,
-Z-Ar'-Y-R4,
-Z-Ar'-X-Y-R4,
-Z-Ar'-Rs, and
-Z-Ar'-X-R 5 ;
Ar is selected from the group consisting of aryl and heteroaryl both of which can
be unsubstituted or can be substituted by one or more substituents independently selected
from the group consisting of alkyl, alkenyl, alkoxy, methylenedioxy, haloalkyl,
haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano, carboxy, formyl,
aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,
heterocyclyl, heterocyclylalkylenyl, amino, aminoalkyl, alkylamino, and dialkylamino;
Ar' is selected from the group consisting of arylene and heteroarylene both of
which can be unsubstituted or can be substituted by one or more substituents
independently selected from the group consisting of alkyl, alkenyl, alkoxy, haloalkyl,
haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano, carboxy, formyl,
aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,
heterocyclyl, heterocyclylalkylenyl, amino, alkylamino, and dialkylamino;
X is selected from the group consisting of alkylene, alkenylene, alkynylene,
arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and
alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene,
or heterocyclylene, and optionally interrupted by one or more -O- groups;
Y is selected from the group consisting of:
-S(0)o- 2 -,
-S(0) 2 -N(R8)-,
-C(R 6 )-,
-C(R 6 )-0-,
-0-C(R 6 )-,
-0-C(0)-0-,
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-N(R 8 )-Q-,
-C(R 6 )-N(R 8 )-,
-0-C(R 6 )-N(R 8 )-,
-C(R 6 )-N(OR 9 )-,
N-Q-
J
-N-C(R 6 )-N-W-
-N— R 7 -N-Q-
— V-N
N-C(R 6 )-N
Z is selected from the group consisting of a bond, alkylene, alkenylene, and
alkynylene;
R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,
arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,
heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,
alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl,
heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups
can be unsubstituted or substituted by one or more substituents independently selected
from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen,
nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy,
heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino,
(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl,
oxo;
R 5 is selected from the group consisting of:
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N-C(R 6 )-I
A
*(CH 2 ) b S
, and
R 6 is selected from the group consisting of =0 and =S;
R7 is C2-7 alkylene;
R 8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and
arylalkylenyl;
R 9 is selected from the group consisting of hydrogen and alkyl;
Rio is C3-8 alkylene;
A is selected from the group consisting of -0-, -C(O)-, -S(O) 0 -2-, -CH 2 -, and
-N(R4)-;
Q is selected from the group consisting of a bond, -C(Re)-, -C(Re)-C(R6), -S(0)2-,
-C(R 6 )-N(R 8 )-W-, -S(0) 2 -N(R 8 )-, -C(R 6 )-0-, and -C(R 6 )-N(OR 9 )-;
V is selected from the group consisting of -CCRe)-, -0-C(R 6 )-, -N(R 8 )-C(R6)- ; and
W is selected from the group consisting of a bond, -C(O)-, and -S(0)2-; and
a and b are independently integers from 1 to 6 with the proviso that a + b is < 7;
or aphaarmaceutically acceptable salt thereof.
For any of the compounds presented herein, each one of the following variables
(e.g., Z, X, Y, R A , Rb, Ri, R2, R3, Q, n, and so on) in any of its embodiments can be
combined with any one or more of the other variables in any of their embodiments and
associated with any one of the formulas described herein, as would be understood by one
of skill in the art. Each of the resulting combinations of variables is an embodiment of the
present invention.
For certain embodiments of Formulas II, IV, V, and VI, n is 0 or 1. For certain
embodiments of Formulas II, IV, V, and VI, n is 0.
For certain embodiments, R is selected from the group consisting of alkyl, alkoxy,
chloro, fluoro, hydroxy, and trifluoromethyl.
For certain embodiments, Rj is selected from the group consisting of -R4,
-X-R4, -X-Y-R4, -X-Y-X-Y-R4, and -X-R 5 .
-S(0) 2 -;
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For certain embodiments, Ri is selected from the group consisting of alkyl,
arylalkylenyl, aryloxyalkylenyl, hydroxyalkyl, fluoroalkyl, heterocyclylalkylenyl which is
unsubstituted or substituted by hydroxy, -X-Y-R4, and -X-R 5 . For certain alternative
embodiments, Ri is selected from the group consisting of alkyl, arylalkylenyl,
5 aryloxyalkylenyl, hydroxyalky, -X-Y-R4, and -X-R 5 . Preferably, X is alkylene.
Preferably, Y is selected from the group consisting of
J- N-Q —
-N(R 8 )-C(0)-, -N(R 8 )-S(0) 2 -, -N(R 8 )-C(0)-N(R 8 )-, -S(0) 2 -, and Kl °
Preferably, R4 is selected from the group consisting of alkyl, aryl, and heteroaryl.
Preferably, R 5 is selected from the group consisting of
^(CH 2 ) a .
-N-C(R 6 ) -N-S(0) 2 _ N(R8) _ C (0)-N A
10 R / , V ,and V (CH 2 ) b ^
For certain embodiments, Ri is selected from the group consisting of alkyl and
hydroxyalkyl.
For certain embodiments, Ri is selected from the group consisting of propyl,
2-methylpropyl, 2-hydroxy-2-methylpropyl, 2,3-dihydroxypropyl,
1 5 2-methyl-2-[(methylsulfonyl)amino]propyl, 4-[(methylsulfonyl)amino]butyl,
4- [(morpholin-4-ylcarbonyl)amino]butyl, ( 1 -hydroxycyclopentyl)methyl,
( 1 -hydroxycyclobutyl)methyl, 2-fluoro-2-methylpropyl, tetrahydro-2if-pyran-4-ylmethyl,
and 4-hydroxytetrahydro -2//-pyran-4-ylmethyl.
For certain embodiments, Ri is selected from the group consisting of propyl,
20 2-methylpropyl, 2-hydroxy-2-methylpropyl, 2,3-dihydroxypropyl,
2-methyl-2-[(methylsulfonyl)amino]propyl, 4-[(methylsulfonyl)amino]butyl, and
2-fluoro-2-methylpropyl .
For certain embodiments, Ri is selected from the group consisting of
2-hydroxy-2-methylpropyl, 2-methylpropyl, propyl, 2,3-dihydroxypropyl,
25 2-methyl-2-[(methylsulfonyl)amino]propyl
(i.e., 2-methanesulfonylamino-2-methylpropyl), and 4-[(methylsulfonyl)amino]butyl
(i.e., 4-methanesulfonylaminobutyl) .
For certain embodiments, R 2 is selected from the group consisting of -R4, -X-R4,
-X-Y-R4, and -X-R 5 .
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For certain embodiments, R 2 is selected from the group consisting of hydrogen,
alkyl, alkoxyalkylenyl, and hydroxyalkylenyl.
For certain embodiments, R 2 is selected from the group consisting of hydrogen,
alkyl, and alkoxyalkylenyl.
5 For certain embodiments, R 2 is selected from the group consisting of hydrogen,
methyl, ethyl, propyl, butyl, methoxymethyl, ethoxymethyl, 2-methoxyethyl,
hydroxymethyl, and 2-hydroxyethyl.
For certain embodiments, R 2 is selected from the group consisting of hydrogen,
methyl, ethyl, propyl, butyl, methoxymethyl, ethoxymethyl, and 2-methoxyethyl. For
10 certain embodiments, R 2 is selected from the group consisting of methyl, ethyl, propyl,
methoxymethyl, ethoxymethyl, and 2-methoxyethyl.
For certain embodiments, R 2 is selected from the group consisting of methyl, ethyl,
propyl, methoxymethyl, ethoxymethyl, 2-methoxyethyl, hydroxymethyl, and
2- hydroxyethyl.
1 5 For certain embodiments, R 3 is selected from the group consisting of -Z-Ar,
-Z-Ar'-Y-Rt, -Z-Ar'-X-Y-Rj, -Z-Ar'-R 5 , and -Z-Ar'-X-R 5 .
For certain embodiments, R3is -Z-Ar.
For certain embodiments, R 3 is selected from the group consisting of phenyl,
pyridyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl, pyrimidinyl, furyl, and quinolinyl; each of
20 which can be unsubstituted or can be substituted by one or more substituents selected from
the group consisting of halogen, alkyl, alkenyl, hydroxy, hydroxyalkyl, alkoxy, amino,
aminoalkyl, cyano, methylenedioxy, arylalkyleneoxy, carboxy, haloalkyl, and
dialkylamino.
For certain other embodiments, R 3 is selected from the group consisting of phenyl,
25 pyridyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl, pyrimidinyl, and furyl; each of which can
be unsubstituted or can be substituted by one or more substituents selected from the group
consisting of halogen, alkyl, alkenyl, hydroxy, hydroxyalkyl, alkoxy, amino, aminoalkyl,
and cyano.
For certain embodiments, R 3 is selected from the group consisting of pyridin-3-yl,
30 pyridin-4-yl, 5-(hydroxymethyl)pyridin-3-yl, 2-ethoxyphenyl,
3- (morpholin-4-ylcarbonyl)phenyl, 3-[(isopropylamino)carbonyl]phenyl,
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3- [(propylamino)carbonyl]phenyl, phenyl, 3-(hydroxymethyl)phenyl, 6-fluoropyridin-3-yl,
4- chlorophenyl, 2-hydroxyphenyl, 2-isopropoxyphenyl, 3,4-difluorophenyl,
3-[(methylsulfonyl)amino]phenyl, 4-[(methylsulfonyl)amino]phenyl, and
3-(aminocarbonyl)phenyl.
5 For certain embodiments, R 3 is selected from the group consisting of pyridin-3-yl
(i.e., 3-pyridyl), pyridin-4-yl (i.e., 4-pyridyl), 5-(hydroxymethyl)pyridin-3-yl
(i.e., 5-hydroxymethyl-3-pyridyl), 2-ethoxyphenyl, and 3-(morpholin-4-ylcarbonyl)phenyl
(i.e., 3-(morpholine-4-carbonyl)phenyl). For certain embodiments, R 3 is selected from the
group consisting of pyridin-3-yl, 3-[(isopropylamino)carbonyl]phenyl,
1 0 3-[(propylamino)carbonyl]phenyl, 3-(morpholin-4-ylcarbonyl)phenyl,
3-[(methylsulfonyl)amino]phenyl, 5-(hydroxymethyl)pyridin-3-yl, and
6-fluoropyridin-3-yl.
For certain other embodimentds, R 3 is -Z-Ar'-Y-R4, -Z-Ar'-X-Y-R4, -Z-Ar'-R 5 , or
-Z-Ar'-X-R 5 . For certain embodiments, R 3 is -Z-Ar'-Y-R*, -Z-Ar'-X- Y-R4, or -Z-Ar'-R 5 .
1 5 Preferably, for certain embodiments, Ar' (of -Z-Ar'-Y-Ri, -Z-Ar'-X- Y-R4,
-Z-Ar'-R 5 , or -Z-Ar'-X-R 5 and more particularly of -Z-Ar'-Y-R}, -Z-Ar'-X- Y-R4, or
-Z-Ar'-R 5 ) is phenylene or pyridylene. Preferably, for certain embodiments, Y in
-Z-Ar'-Y-R4 or -Z-Ar'-X- Y-R4 is selected from the group consisting of: -S(0)o-2-,
-S(0) 2 -N(R 8 )-, -C(O)-, -N(R 8 )-Q-, -C(R 6 )-N(R 8 )-, -C(0)-O-, and -C(0)-N(OCH 3 )-.
20 Preferably, for certain embodiments, Y in -Z-At'-Y-Pm or -Z-Ar'-X- Y-R4 is selected from
the group consisting of -S(O) 0 . 2 -, -C(O)-, -N(R 8 )-Q-, and -C(R 6 )-N(R 8 )-. Preferably, in
such embodiments, Q is selected from the group consisting of bond, -C(O)-, -C(0)-0-,
-C(0)-N(H)-, and -S(0) 2 -. Moe preferably, in such embodiments, Q is selected from the
group consisting of a bond, -C(O)-, -C(0)-0, and -S(0) 2 -. Preferably, in such
25 embodiments, R 8 is selected from the group consisting of hydrogen, C1-4 alkyl, and
alkoxyalkylenyl. Preferably, for certain embodiments, X in -Z-Ar'-X- Y-R4 or -Z-Ar'-X-Rs
(more particularly in -Z-Ar'-X- Y-R4) is Ci-4alkylene. Preferably, for certain
embodiments, R4 in -Z-At'-Y-Pm or -Z-At'-X-Y-Pm is selected from the group consisting of
alkyl, aryl, arylalkylenyl, heteroarylalkylenyl, heteroaryl, and heterocyclyl. Preferably, for
30 certain other embodiments, R4 in -Z-Ar'-Y-Rt or -Z-At'-X-Y-Pm is selected from the group
consisting of alkyl, haloalkyl, aryl, arylalkylenyl, heteroarylalkylenyl, heteroaryl,
alkylheteroarylenyl, and heterocyclyl, preferably, with the proviso that R4 may also be
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hydrogen when Y is -C(0)-0-, -C(0)-N(OCH 3 )-, or -N(R 8 )-. Preferably, for certain
embodiments, R 5 in -Z-Ar'-R 5 or -Z-Ar'-X-R 5 (more particularly in -Z~Ar'-R 5 ) is
For certain embodiments, R 3 is selected from the group consisting of pyridin-3-yl
(i.e., 3-pyridyl), 3-[(isopropylamino)carbonyl]phenyl, 3-[(propylamino)carbonyl]phenyl,
and 3-(morpholin-4-ylcarbonyl)phenyl (i.e., 3-(morpholine-4-carbonyl)plienyl).
For certain embodiments, R4 is selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl,
heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl
wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,
heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and
heterocyclyl groups can be unsubstituted or substituted by one or more sTibstituents
independently selected from the group consisting of alkyl, alkoxy, hydro xyalkyl,
haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,
arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino,
carboxy, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and in ttie case of alkyl,
alkenyl, alkynyl, and heterocyclyl, oxo.
For certain embodiments, R4 is selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl,
heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl
wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,
heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and
heterocyclyl groups can be unsubstituted or substituted by one or more sxibstituents
independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl,
haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,
arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino,
alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and in the case of* alkyl, alkenyl,
alkynyl, and heterocyclyl, oxo.
For certain embodiments, R4 is selected from the group consisting of alkyl, aryl,
and heteroaryl. For certain embodiments, particularly in -Z-Ar'-Y-Rj or -Z-Ar'-X-Y-R),
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R4 is selected from the group consisting of alkyl, haloalkyl, aryl, arylalkylenyl,
heteroarylalkylenyl, heteroaryl, alkylheteroarylenyl, and heterocyclyl, preferably with the
proviso that R4 may also be hydrogen when Y is -C(0)-O, -C(0)-N(OCH 3 )-, or -N(R 8 )-.
For certain embodiments, particularly in -Z-Ar'-Y-Rt or -Z-Ar'-X-Y-R4, R4 is selected
5 from the group consisting of alkyl, aryl, arylalkylenyl, heteroarylalkylenyl, heteroaryl, and
heterocyclyl.
For certain embodiments, R 5 is selected from the group consisting of:
WCH 2 ) a . /-^ ^(CHz^
-N-C(R 6 ) -N-S(0) 2 _ v _,{ \ -f N-C(R 6 )-N A
For certain embodiments, R 5 is selected from the group consisting of
^(CH 2 ) a .
-N-O0V) -N-S(0) 2 - N( r 8 )-C(0)-N A
R 7 y , W ,and V (CH 2 ) b -^
For certain embodiments, particularly in -Z-Ar'-Rs or -Z-Ar'-X-R 5 , R5 is
\CH 2 ) b -^
For certain embodiments, X is selected from the group consisting of alkylene,
alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene,
alkenylene, and alkynylene groups can be optionally interrupted or terminated with
arylene, heteroarylene, or heterocyclylene, and optionally interrupted by one or more -O-
groups.
For certain embodiments, X is alkylene.
For certain embodiments, particularly in -Z-Ar'-X-Y-R4 or -Z-Ar -X-R 5 , X is C1-4
alkylene.
For certain embodiments, Y is selected from the group consisting of -S(0)o-2-,
-S(0) 2 -N(R 8 )-, -C(R 6 )-, -C(R 6 )-0-, -0-C(R6)-, -0-C(0)-0, -N(R 8 )-Q-, -C(R 6 )-N(R 8 )-,
-0-C(Re)-N(R 8 )-, -C(R 6 )-N(OR 9 )-, % K ™ , 11 (CH2) °" 2
(CH 2 ) (
'2/0-2
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For certain embodiments, Y is selected from the group consisting of -S(O) 0 -2-,
-S(0) 2 -N(R 8 )-, -C(R6)-, -C(R 6 )-0-, -0-C(R6)-, -0-C(0)-0-, -N(R 8 )-Q-, -C(R 6 )-N(R 8 )-,
5 -0-C(R6)-N(R 8 )-, -C(R 6 )-N(OR 9 )-,
For certain embodiments, Y is selected from the group consisting of S(O) 0 -2-,
-C(O)-, -N(R 8 )-Q-, and -C(R 6 )-N(R 8 )-.
For certain embodiments, particularly in -Z-Ar'-Y-R* or -Z-Ar'-X-Y-Ri, Y is
1 0 selected from the group consisting of -S(O) 0 - 2 -, -S(0) 2 -N(R 8 )-, -C(O)-, -N(R 8 )-Q-,
-C(R 6 )-N(R 8 )-, -C(0)-0-, and -C(0)-N(OCH 3 )-.
For certain embodiments, particularly in -Z-Ar'-Y-R* or -Z-Ar'-X-Y-Rj, Y is
selected from the group consisting of -S(O) 0 - 2 -, -C(O)-, -N(Rs)-Q-, and -C(R 6 )-N(R 8 )-.
For certain embodiments, Y is selected from the group consisting of -N(R 8 )-C(0)-,
-C N-Q —
V R J
15 -N(R 8 )-S(0) 2 -, -N(R 8 )-C(0)-N(R 8 )-, -S(0) 2 -, and Kl °
For certain embodiments, Z is selected from the group consisting of a bond,
alkylene, alkenylene, and alkynylene. For certain embodiments, Z is selected from the
group consisting of a bond, methylene, and ethylene. For certain embodiments, Z is a
bond.
20 For certain embodiments, Ar is selected from the group consisting of aryl and
heteroaryl both of which can be unsubstituted or can be substituted by one or more
substituents independently selected from the group consisting of alkyl, alkenyl, alkoxy,
methylenedioxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto,
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cyano, carboxy, formyl, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy,
heteroarylalkyleneoxy, heterocyclyl, heterocyclylalkylenyl, alkoxyalkylenyl,
a-aminocarboxyalkylenyl, amino, aminoalkyl, alkylamino, and dialkylamino.
For certain embodiments, Ar is selected from the group consisting of aryl and
5 heteroaryl both of which can be unsubstituted or can be substituted by one or more
substituents independently selected from the group consisting of alkyl, alkenyl, alkoxy,
methylenedioxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto,
cyano, carboxy, formyl, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy,
heteroarylalkyleneoxy, heterocyclyl, heterocyclylalkylenyl, amino, aminoalkyl,
10 alkylamino, and dialkylamino.
For certain embodiments of Formulas I, II, and III, Ar may also be aryl or
heteroaryl substituted by alkoxyalkylenyl.
For certain embodiments, Ar' is selected from the group consisting of arylene and
heteroarylene both of which can be unsubstituted or can be substituted by one or more
15 substituents independently selected from the group consisting of alkyl, alkenyl, alkoxy,
haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano, carboxy,
formyl, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,
heterocyclyl, heterocyclylalkylenyl, amino, alkylamino, and dialkylamino.
For certain embodiments, particularly in -Z-Ar'-Y-Rt, -Z-Ar'-X-Y-R4, or
20 -Z-Ar'-R 5 , Ar' is phenylene or pyridylene.
For certain embodiments, Q is selected from the group consisting of a bond,
-C(R 6 )-, -C(R6)-C(R6), -S(0) 2 -, -C(R 6 )-N(R 8 )-W-, -S(0) 2 -N(R 8 )-, -C(R 6 )-0-, and
-C(R 6 )-N(OR 9 )-. For certain embodiments, particularly embodiments of -N(Rg)-Q-, Q is
selected from the group consisting of a bond, -C(O)-, -C(0)-0-, -C(0)-N(H)-, and
25 -S(0)2-. For certain embodiments, particularly embodiments of -N(Rs)-Q-, Q is selected
from the group consisting of a bond, -C(O)-, -C(0)-0-, and -S(0) 2 -. For certain
embodiments, Q is selected from the group consisting of -C(O)-, -C(0)-N(Rg)-, and
-S(0) 2 -.
For certain embodiments, R 6 is =0 or =S. For certain embodiments, R 6 is =0.
30 For certain embodiments, R 7 is C 2 . 7 alkylene. For certain embodiments, R 7 is
C 2 _3 alkylene.
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For certain embodiments, R 8 is selected from the group consisting of hydrogen,
alkyl, alkoxyalkylenyl, and arylalkylenyl. For certain embodiments, particularly in
-N(R 8 )-Q- and -C(R6)-N(R 8 )-, R 8 is selected from the group consisting of hydrogen,
C1-4 alkyl, and alkoxyalkylenyl. For certain embodiments, R 8 is hydrogen.
5 For certain embodiments, R9 is hydrogen or alkyl. For certain embodiments, R 9 is
hydrogen or methyl.
For certain embodiments, Rio is C 3 -g alkylene. For certain embodiments, Ri 0 is
C 5 alkylene.
For certain embodiments, R n is selected from the group consisting of fluoro,
10 hydroxy, and alkoxy.
For certain embodiments, A is selected from the group consisting of -0-, -C(O)-,
-S(0)o- 2 -, -CH 2 -, and -NCEU)-. For certain embodiments, A is -0-, -CH 2 -, or -C(O)-.
For certain embodiments, V is selected from the group consisting of -C(Re)-,
-0-C(R 6 )-, -N(R 8 )-C(R 6 )-, and -S(0) 2 -. For certain embodiments, V is -C(O)-. For certain
15 embodiments, V is -N(R 8 )-C(R 6 )-. For certain embodiments, Vis -S(0) 2 -.
For certain embodiments, W is selected from the group consisting of a bond,
-C(O)-, and -S(0) 2 -. For certain embodiments, W is a bond.
For certain embodiments, a and b are independently integers from 1 to 6 with the
proviso that a + b is < 7.
20 For certain embodiments, a is 2.
For certain embodiments, b is 2.
For certain embodiments of the compounds of Formulas (I) through (VI), the
-NH 2 group can be replaced by an -NH-G group, as shown in the compound of Formula
(VII), to form prodrugs. In such embodiments, G is selected from the group consisting of:
25 -C(0)-R', a-aminoacyl, a-aminoacyl-a-aminoacyl, -C(0)-0-R', -C(0)-N(R")R',
-C(=NY')-R', -CH(OH)-C(0)-OY', -CH(OCi_4 alkyl)Y 0 , -CH 2 Yi, and -CH(CH 3 )Yi. For
certain embodiments, G is selected from the group consisting of -C(0)-R', a-aminoacyl,
a-aminoacyl-a-aminoacyl, and -C(0)-0-R\ Preferably, R' and R" are independently
selected from the group consisting of Cmo alkyl, C3-7 cycloalkyl, and benzyl, each of
30 which may be unsubstituted or substituted by one or more substitutents selected from the
group consisting of halogen, hydroxy, nitro, cyano, carboxy, C1-6 alkyl, Cm alkoxy, aryl,
heteroaryl, arylCi-4 alkylenyl, heteroarylCi-4 alkylenyl, haloCi.4 alkylenyl,
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haloCi-4 alkoxy, -0-C(0)-CH 3 , -C(0)-0-CH 3 , -C(0)-NH 2 , -0-CH 2 -C(0)-NH 2 , -NH 2 , and
-S(0) 2 -NH 2 , with the proviso that R" can also be hydrogen. Preferably, a-aminoacyl is an
acyl group derived from an amino acid selected from the group consisting of racemic, D-,
and L-amino acids. Preferably, Y' is selected from the group consisting of hydrogen,
5 Ci-6 alkyl, and benzyl. Preferably, Y 0 is selected from the group consisting of Ci_ 6 alkyl,
carboxyCi-e alkylenyl, aminoCi-4 alkylenyl, mono-jV-Ci- 6 alkylaminoCi- 4 alkylenyl, and
di-TViiV-Ci-e alkylaminoCi-4 alkylenyl. Preferably, Y1 is selected from the group consisting
of mono-JV-Ci-e alkylamino, di-N,N-Ci^ alkylamino, morpholin-4-yl, piperidin-l-yl,
pyrrolidin-l-yl, and 4-Ci-4alkylpiperazin-l-yl.
10 In one embodiment, there is provided a pharmaceutical composition containing an
effective amount of a compound of Formula VII. In one embodiment, there is provided a
method of inducing cytokine biosynthesis in an animal by administering an effective
amount of a compound of Formula VII to the animal. In one embodiment, there is
provided a method of treating a viral infection in an animal by administering an effective
1 5 amount of a compound of Formula VII to the animal. In one embodiment, there is
provided a method of treating a neoplastic disease in an animal by administering an
effective amount of a compound of Formula VII to the animal.
As used herein, the terms "alkyl," "alkenyl," "alkynyl" and the prefix
20 "alk-" are inclusive of both straight chain and branched chain groups and of cyclic groups,
e.g., cycloalkyl and cycloalkenyl. Unless otherwise specified, these groups contain from 1
to 20 carbon atoms, with alkenyl groups containing from 2 to 20 carbon atoms, and
alkynyl groups containing from 2 to 20 carbon atoms, hi some embodiments, these groups
have a total of up to 10 carbon atoms, up to 8 carbon atoms, up to 6 carbon atoms, up to 5
25 carbon atoms, or up to 4 carbon atoms. Cyclic groups can be monocyclic or polycyclic
and preferably have from 3 to 10 ring carbon atoms. Exemplary cyclic groups include
cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl, adamantyl, and substituted and
^substituted bornyl, norbornyl, and norbornenyl.
Unless otherwise specified, "alkylene," "alkenylene," and "alkynylene" are the
30 divalent forms of the "alkyl," "alkenyl," and "alkynyl" groups defined above. Likewise,
"alkylenyl," "alkenylenyl," and "alkynylenyl" are the divalent forms of the "alkyl,"
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"alkenyl," and "alkynyl" groups defined above. For example, an arylalkylenyl group
comprises an alkylene moiety to which an aryl group is attached.
The term "haloalkyl" is inclusive of groups that are substituted by one or more
halogen atoms, including perfluorinated groups. This is also true of other groups that
5 include the prefix "halo-". Examples of suitable haloalkyl groups are chloromethyl,
trifluoromethyl, and the like.
The term "aryl" as used herein includes carbocyclic aromatic rings or ring systems.
Examples of aryl groups include phenyl, naphthyl, biphenyl, fluorenyl and indenyl.
The term "heteroatom" refers to the atoms O, S, or N.
10 The term "heteroaryl" includes aromatic rings or ring systems that contain at least
one ring heteroatom (e.g., O, S, N). In some embodiments, the term "heteroaryl" includes
a ring or ring system that contains 2 to 12 carbon atoms, 1 to 3 rings, 1 to 4 heteroatoms,
and O, S, and/or N as the heteroatoms. Suitable heteroaryl groups include furyl, thienyl,
pyridyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, triazolyl, pyrrolyl, tetrazolyl,
15 imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzofuranyl, benzothiophenyl, carbazolyl,
benzoxazolyl, pyrimidinyl, benzimidazolyl, quinoxalinyl, benzothiazolyl, naphthyridinyl,
isoxazolyl, isothiazolyl, purinyl, quinazolinyl, pyrazinyl, 1-oxidopyridyl, pyridazinyl,
triazinyl, tetrazinyl, oxadiazolyl, thiadiazolyl, and so on.
The term "heterocyclyl" includes non-aromatic rings or ring systems that contain at
20 least one ring heteroatom (e.g., O, S, N) and includes all of the fully saturated and partially
unsaturated derivatives of the above mentioned heteroaryl groups. In some embodiments,
the term "heterocyclyl" includes a ring or ring system that contains 2 to 12 carbon atoms, 1
to 3 rings, 1 to 4 heteroatoms, and O, S, and N as the heteroatoms. Exemplary
heterocyclic groups include pyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl,
25 1,1 -dioxothiomorpholinyl, piperidinyl, piperazinyl, thiazolidinyl, imidazolidinyl,
isothiazolidinyl, tetrahydropyranyl, quinuclidinyl, homopiperidinyl (azepanyl), 1,4-
oxazepanyl, homopiperazinyl (diazepanyl), 1,3-dioxolanyl, aziridinyl, azetidinyl,
dihydroisoquinolin-(l J fZ)-yl, octahydroisoquinolin-(l//)-yl, dihydroquinolin-(2 J f/)-yl,
octahydroquinolin-(2//)-yl, dihydro-l/f-irnidazolyl, 3-azabicyclo[3.2.2]non-3-yl, and the
30 like.
The term "heterocyclyl" includes bicylic and tricyclic heterocyclic ring systems.
Such ring systems include fused and/or bridged rings and spiro rings. Fused rings can
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include, in addition to a saturated or partially saturated ring, an aromatic ring, for example,
a benzene ring. Spiro rings include two rings joined by one spiro atom and three rings
joined by two spiro atoms.
When "heterocyclyl" contains a nitrogen atom, the point of attachment of the
5 heterocyclyl group may be the nitrogen atom.
The terms "arylene," "heteroarylene," and "heterocyclylene" are the divalent forms
of the "aryl," "heteroaryl," and "heterocyclyl" groups defined above. Likewise, "arylenyl,"
"heteroarylenyl," and "heterocyclylenyl" are the divalent forms of the "aryl," "heteroaryl,"
and "heterocyclyl" groups defined above. For example, an alkylarylenyl group comprises
10 an arylene moiety to which an alkyl group is attached.
When a group (or substituent or variable) is present more than once in any Formula
described herein, each group (or substituent or variable) is independently selected, whether
explicitly stated or not. For example, for the formula -N(R 8 )-C(0)-N(R 8 )- each R 8 group
is independently selected. In another example, when an R 2 and an R 3 group both contain
15 an R4 group, each R4 group is independently selected. In a further example, when more
than one Y group is present (i.e., R 2 and R 3 both contain a Y group) and each Y group
contains one or more R 7 groups, then each Y group is independently selected, and each R 7
group is independently selected.
The invention is inclusive of the compounds described herein in any of their
20 pharmaceutically acceptable forms, including isomers (e.g., diastereomers and
enantiomers), salts, solvates, polymorphs, prodrugs, and the like. In particular, if a
compound is optically active, the invention specifically includes each of the compound's
enantiomers as well as racemic mixtures of the enantiomers. It should be understood that
the term "compound" includes any or all of such forms, whether explicitly stated or not
25 (although at times, "salts" are explicitly stated).
The term "prodrug" means a compound that can be transformed in vivo to yield an
immune response modifying compound in any of the salt, solvated, polymorphic, or
isomeric forms described above. The prodrug, itself, may be an immune response
modifying compound in any of the salt, solvated, polymorphic, or isomeric forms
30 described above. The transformation may occur by vaious mechanisms, such as through a
chemical (e.g., solvolysis or hydrolysis, for example, in the blood) or enzymatic
biotransformation. A discussion of the use of prodrugs is provided by T. Higuchi and W.
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Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A. C. S. Symposium Series,
and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American
Pharmaceutical Association and Pergamon Press, 1987.
5 Preparation of the Compounds
Compounds of the invention may be synthesized by synthetic routes that include
processes analogous to those well known in the chemical arts, particularly in light of the
description contained herein. The starting materials are generally available from
commercial sources such as Aldrich Chemicals (Milwaukee, Wisconsin, USA) or are
1 0 readily prepared using methods well known to those skilled in the art (e.g., prepared by
methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic
Synthesis, v. 1-19, Wiley, New York, (1967-1999 ed.); Alan R. Katritsky, Otto Meth-
Cohn, Charles W. Rees, Comprehensive Organic Functional Group Transformations, v. 1-
6, Pergamon Press, Oxford, England, (1995); Barry M. Trost and Ian Fleming,
15 Comprehensive Organic Synthesis, v. 1-8, Pergamon Press, Oxford, England, (1991); or
Beilsteins Handbuch der organischen Chemie, 4, Aufl. Ed. Springer- Verlag, Berlin,
Germany, including supplements (also available via the Beilstein online database)).
For illustrative purposes, the reaction schemes depicted below provide potential
routes for synthesizing the compounds of the present invention as well as key
20 intermediates. For more detailed description of the individual reaction steps, see the
EXAMPLES section below. Those skilled in the art will appreciate that other synthetic
routes may be used to synthesize the compounds of the invention. Although specific
starting materials and reagents are depicted in the reaction schemes and discussed below,
other starting materials and reagents can be easily substituted to provide a variety of
25 derivatives and/or reaction conditions. In addition, many of the compounds prepared by
the methods described below can be further modified in light of this disclosure using
conventional methods well known to those skilled in the art.
In the preparation of compounds of the invention it may sometimes be necessary to
protect a particular functionality while reacting other functional groups on an intermediate.
30 The need for such protection will vary depending on the nature of the particular functional
group and the conditions of the reaction step. Suitable amino protecting groups include
acetyl, trifluoroacetyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl, and 9-
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fluorenylmethoxycarbonyl (Fmoc). Suitable hydroxy protecting groups include acetyl and
silyl groups such as the tert-butyl dimethylsilyl group. For a general description of
protecting groups and their use, see T. W. Greene and P. G. M. Wuts, Protective Groups
in Organic Synthesis, John Wiley & Sons, New York, USA, 1991.
5 Conventional methods and techniques of separation and purification can be used to
isolate compounds of the invention or pharmaceutically acceptable salts thereof, as well as
various intermediates related thereto. Such techniques may include, for example, all types
of chromatography (high performance liquid chromatography (HPLC), column
chromatography using common absorbents such as silica gel, and thin layer
10 chromatography), recrystallization, and differential (i.e., liquid-liquid) extraction
techniques.
Compounds of the invention can be prepared according to Reaction Scheme I
where R 3a is -Z a -Ar, -Z a -Ar'-Y-R4, -Za-Ar'-XI-Y-R^ or- Za-Ar'-Rs; Z a is a bond, alkenylene,
or alkynylene; Hal is bromo or iodo; and R, n, Ar, Ar', X, Y, R4, and R 5 are as defined
15 above. Ri a and R 2 b are subsets of Ri and R 2 as defined above that do not include those
substituents that one skilled in the art would recognize as being susceptible to oxidation in
step (8). These substituents include -S- and heteroaryl groups.
In step (1) of Reaction Scheme I, an aminopyridine of Formula X is treated with
the condensation product generated from 2,2-dimethyl-l,3-dioxane-4,6-dione (Meldrum's
20 acid) and tri ethyl orthoformate to provide an imine of Formula XI. The reaction is
conveniently carried out by adding a solution of an aminopyridine of Formula X to a
heated mixture of Meldrum's acid and triethyl orthoformate and heating the reaction at an
elevated temperature, such as 70 °C. Aminopyridines of Formula X are commercially
available, or they can be prepared by known methods.
25 In step (2) of Reaction Scheme I, an imine of Formula XI undergoes thermolysis
and cyclization to provide a [l,5]naphthyridin-4-ol of Formula XII. The reaction is
conveniently carried out in a medium such as DOWTHERM A heat transfer fluid at a
temperature not lower than about 200 °C and not higher than about 250 °C.
In step (3) of Reaction Scheme I, the [l,5]naphthyridin-4-ol of Formula XII is
30 nitrated under conventional nitration conditions to provide a 3-nitro[l ,5]naphthyridin-4-ol
of Formula XIII. The reaction is conveniently carried out by heating the
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[l,5]naphthyridin-4-ol of Formula XII in nitric acid at an elevated temperature, such as 90
°C.
In step (4) of Reaction Scheme I, a 3-mtro[l,5]naphthyridin-4~ol of Formula XIII
is chlorinated using conventional chlorination chemistry to provide a
5 4-chloro-3-nitro[l,5]naphthyridine of Formula XIV. The reaction is conveniently carried
out by treating the 3-nitro[l,5]naphthyridin-4-ol of Formula Kill with phosphorous
oxychloride in a suitable solvent, such as A^iV-dimethylformaniide (DMF). The reaction
can be carried out at ambient temperature or at an elevated temperature, such as 100 °C.
In step (5) of Reaction Scheme I, a 4-chloro-3-nitro[l,5]naphthyridine of Formula
10 XIV is treated with an amine of Formula Ri a -NH 2 to provide a 3~nitro[l,5]naphthyridin-4-
amine of Formula XV. Several amines of Formula R ]a -NH 2 are commercially available;
others can be prepared by known synthetic methods. The reaction is conveniently carried
out by adding the amine of Formula Ri a -NH 2 to a solution of the 4-chloro-3-
nitro[l,5]naphthyridine of Formula XIV in a suitable solvent, such as dichloromethane or
15 methanol, in the presence of a tertiary amine, such as triethylamine. The reaction can be
carried out at ambient temperature or at a sub-ambient temperature such as, for example, 0
°C.
In step (6) of Reaction Scheme I, a 3-nitro[l,5]naphthyridin-4-amine of Formula
XV is reduced to provide a [l,5]naphthyridine-3,4-diamine of Formula XVI. The reaction
20 can be carried out by hydrogenation using a heterogeneous hydrogenation catalyst such as
platinum on carbon. The hydrogenation is conveniently carried out in a Parr apparatus in
a suitable solvent, such as toluene, methanol, or acetonitrile, or a suitable solvent mixture,
such as acetonitrilermethanol or acetonitrilerisopropyl alcohol. The reaction can be carried
out at ambient temperature.
25 Alternatively, the reduction in step (6) can be carried out using a one- or two-phase
sodium dithionite reduction. The reaction is conveniently carried out using the conditions
described by Park, K.K.; Oh, C.H.; and Joung, W. K.; Tetrahedron Lett, 34, pp. 7445-
7446 (1993) by adding sodium dithionite to a compound of Formula XV in a mixture of
dichloromethane and water at ambient temperature in the presence of potassium carbonate
30 and ethyl viologen dibromide, ethyl viologen diiodide, or 1 , 1 '-di-«-octyl-4,4'-bipyridinium
dibromide.
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In step (7) of Reaction Scheme I, a [l,5]naphthyridine-3,4-diamine of Formula
XVI is treated with a carboxylic acid equivalent to provide a l#-imidazo[4,5-
c][l,5]naphthyridine of Formula XVII. Suitable carboxylic acid equivalents include
orthoesters of Formula R 2a C(0-alkyl) 3 , 1,1-dialkoxyalkyl alkanoates of Formula
5 R 2a C(0-alkyl) 2 (0-C(0)-alkyl), and acid chlorides of Formula R 2a C(0)Cl. The selection of
the carboxylic acid equivalent is determined by the desired substituent at R 2a . For
example, triethyl orthofonnate will provide a compound where R 2a is hydrogen, and
trimethyl orthovalerate will provide a compound where R 2a is a butyl group. The reaction
is conveniently carried out by adding the carboxylic acid equivalent to a
10 [1 ,5]naphthyridine-3 ,4-diamine of Formula XVI in a suitable solvent, such as tobuene or
xylenes. Optionally, catalytic pyridine hydrochloride can be added. The reaction is
carried out at a temperature high enough to drive off alcohol or water formed during the
reaction. Conveniently, a Dean-Stark trap can be used to collect the volatiles.
Alternatively, step (7) can be carried out in two steps when an acid chloride of
15 Formula R 2a C(0)Cl is used as the carboxylic acid equivalent. Part (i) of step (7) is
conveniently carried out by adding the acid chloride to a solution of a [l,5]naphtriyridine-
3,4-diamine of Formula XVI in a suitable solvent, such as dichloromethane, chloroform,
or acetonitrile, or mixtures thereof, to afford an amide. Optionally, a tertiary amine, such
as triethylamine, pyridine, or 4-dimethylaminopyridine, can be added. The reaction can be
20 carried out at ambient temperature. The amide product can be isolated and optionally
purified using conventional techniques. Part (ii) of step (7) can be carried out by heating,
for example, at reflux, the amide prepared in part (i) to provide a l#-imidazo[4,5-
c][l,5]naphthyridine of Formula XVII. The reaction is conveniently carried out in a
suitable solvent, such as toluene, at a temperature sufficient to drive off water formed
25 during the reaction. The reaction can also be carried out in a solvent, such as etkanol or
methanol, in the presence of a base, such as triethylamine or aqueous potassium carbonate.
In step (8) of Reaction Scheme I, a li/-imidazo[4,5-c][l,5]naphthyridine of
Formula XVII is oxidized to provide a l/Z-imidazo[4,5-c][l,5]naphthyridine-5iV-oxide of
Formula XVIII using a conventional oxidizing agent capable of forming /Y-oxides. The
30 reaction is conveniently carried out by adding 3-chloroperoxybenzoic acid to a solution of
a compound of Formula XVII in a solvent, such as dichloromethane or chloroform. The
reaction can be carried out at ambient temperature.
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In step (9) of Reaction Scheme I, a l//-imidazo[4,5-c][l,5]naphthyridine-5A/-oxide
of Formula XVIII is aminated to provide a l//-imidazo[4,5-c][l,5]naphthyridin-4-amine
of Formula XIX. Step (9) can be carried out by the activation of an JV-oxide of Formula
XVIII by conversion to an ester and then reacting the ester with an aminating agent.
5 Suitable activating agents include alkyl- or arylsulfonyl chlorides, such as benzenesulfonyl
chloride, methanesulfonyl chloride, or/?-toluenesulfonyl chloride. Suitable aminating
agents include ammonia, in the form of ammonium hydroxide, for example, and
ammonium salts, such as ammonium carbonate, ammonium bicarbonate, and ammonium
phosphate. The reaction is conveniently carried out by adding ammonium hydroxide to a
10 solution of the TV-oxide of Formula XVIII in a suitable solvent, such as dichloromethane or
chloroform, and then adding p-toluenesulfonyl chloride. The reaction can be carried out at
ambient temperature.
Steps (8) and (9) can alternatively be combined and carried out as a one-pot
procedure by adding 3-chloroperoxybenzoic acid to a solution of a compound of Formula
15 XVII in a solvent, such as dichloromethane or chloroform, and then adding ammonium
hydroxide and />-toluenesulfonyl chloride without isolating the iV-oxide of Formula XVIII.
Step (10) of Reaction Scheme I can be carried out using known palladium-
catalyzed coupling reactions, such as the Suzuki coupling, the Stille coupling, the
Sonogashira coupling, and the Heck reaction. For example, a l#-imidazo[4,5-
20 c] [ 1 ,5]naphthyridin-4-amine of Formula XIX undergoes Suzuki coupling with a boronic
acid of Formula R 3a -B(OH) 2 , an anhydride thereof, or a boronic acid ester of Formula
R 3a -B(0-alkyl) 2 to provide an l J f/-imidazo[4,5-c][l,5]naphthyridin-4-amine of Formula
Ha, a subgenus of Formulas I and II, wherein R 3a is as defined above and Z a is a bond or
alkenylene. The coupling is carried out by combining a li/-imidazo[4,5-
25 c] [ 1 ,5]naphthyridin-4-amine of Formula XIX with a boronic acid or an ester or anhydride
thereof in the presence of palladium (II) acetate, triphenylphosphine, and a base, such as
sodium carbonate or sodium bicarbonate, in a suitable solvent or solvent mixture, such as
«-propanol:water. The coupling reaction may also conveniently carried out by heating a
mixture of a compound of Formula XIX, a boronic acid or an ester or anhydride thereof,
30 potassium carbonate and catalytic dichlorobis(triphenylphosphine)palladium(II) in a
suitable solvent or solvent mixture, such as dimethoxyethane (DME) and water. Suzuki
coupling reactions may be carried out under an inert atmosphere, such as nitrogen or
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argon. The reactions can be carried out at an elevated temperature, for example, at the
reflux temperature of the solvent, typically at a temperature not lower than 80 °C and not
higher than 120 °C. Numerous boronic acids of Formula R 3a -B(OH) 2 , anhydrides thereof,
and boronic acid esters of Formula R 3a -B(0-alkyl) 2 are commercially available; others can
5 be readily prepared using known synthetic methods. See, for example, Li, W. et al, J.
Org. Chem., 67, 5394-5397 (2002).
The Heck reaction can also be used in step (10) of Reaction Scheme I to provide
compounds of Formula Ha, wherein R 3a is as defined above and -Z a is alkenylene. The
Heck reaction is carried out by coupling a li7-imidazo[4,5-c][l,5]naphthyridin-4-amine of
1 0 Formula XIX with a compound of the Formula H 2 C=C(H)-Ar a , wherein Ar a is -Ar,
-Ar'-Y-Ri, -Ar'-X-Y-Rt, or -Ar'-R 5 . Several of these vinyl-substituted compounds, for
example, compounds of the Formulas H 2 C=C(H)-Ar, H 2 C=C(H)-Ar'-Y-R4, and
H 2 C=C(H)-Ar'-X-Y-R4 are commercially available; others can be prepared by known
methods. The reaction is conveniently carried out by combining the l#-imidazo[4,5-
15 c][l,5]naphthyridin-4-amine of Formula XIX and the vinyl-substituted compound in the
presence of palladium (II) acetate, triphenylphosphine or tri-ort/zo-tolylphosphine, and a
base, such as triethylamine, in a suitable solvent, such as acetonitrile or toluene. The
reaction can be carried out at an elevated temperature not lower than 80 °C and not higher
than about 120 °C under an inert atmosphere.
20 Compounds of Formula Ha, wherein R 3a is defined as above Z a is alkynylene, can
also be prepared by palladium catalyzed coupling reactions, such as the Stille coupling or
Sonogashira coupling. These reactions are carried out by coupling a l#-imidazo[4,5-
c][l,5]naphthyridin-4-amine of Formula XIX with a compound of the Formula H-C=C-Ar,
(alkyl) 3 Sn-C=C-Ar, or (alkyl) 3 Si-C=C-Ar, wherein Ar is as defined above.
25 Isomers of the compound of Formula X or Formula XII are also available or can be
synthesized and can be used to prepare compounds of Formulas IV, V, and VI according
to the methods shown in Reaction Scheme I.
For some embodiments, compounds in Reaction Scheme I can be further
elaborated using conventional synthetic methods. For example, an amine of Formula
30 Ri a -NH 2 may be substituted by a hydroxy or second amino group, which may be further
functionalized before step (7) of Reaction Scheme I or later in the synthetic route. Several
examples of synthetic elaborations of an R la group on a li?-imidazo[4,5-c]quinoline or a
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lff-imidazo[4,5-c]naphthyridine are known and can be used to provide a compound of
Formula II wherein Ri is as defined above. See, for example, U.S. Patent Nos. 4,689,338
(Gerster), 4,929,624 (Gerster et al.), 5,268,376 (Gerster), 5,389,640 (Gerster et al.),
6,194,425 (Gerster et al), 6,331,539 (Crooks et al.), 6,451,810 (Coleman et al.), 6,541,485
5 (Crooks et al.), 6,660,747 (Crooks et al.), 6,670,372 (Charles et al.), 6,683,088 (Crooks et
al.), 6,656,938 (Crooks et al.), 6,664,264 (Dellaria et al.), 6,677,349 (Griesgraber), and
6,664,260 (Charles et al), and U.S. Patent Publication Application No. US 2004/0147543
(Hays et al.).
Similar synthetic transformations can be made at R 2a if, for example, the acid
10 chloride used in step (7) of Reaction Scheme I contains a protected hydroxy or amino
group, and these synthetic transformations can be used to provide compounds of Formula
II, wherein R2 is as defined above. Some acid chlorides of this type are commercially
available; others can be prepared by known synthetic methods. A protected hydroxy or
amino group thus installed at the R 2a position can then be deprotected by a variety of
15 methods well known to one of skill in the art. For example, a hydroxyalkylenyl group is
conveniently introduced at the R 2a position by the dealkylation of a methoxy- or
ethoxyalkylenyl group, which can be installed by using a methoxy- or ethoxy-substituted
carboxylic acid equivalent, for example, methoxyacetyl chloride, 2-methoxypropionyl
chloride, or ethoxyacetyl chloride, in step (7) of Reaction Scheme I or step (3) in Reaction
20 Scheme II below. The dealkylation can be carried out by treating a compound wherein R 2a
is an alkoxyalkylenyl group with boron tribromide in a suitable solvent such as
dichloromethane at a sub-ambient temperature such as 0 °C. Alternatively, acetoxyacetyl
chloride can be used in step (7) of Reaction Scheme I, and hydrolysis of the ester group to
reveal a hydroxy group can be carried out by conventional methods. The resulting
25 hydroxy group may then be oxidized to an aldehyde or carboxylic acid or converted to a
leaving group such as, for example, a chloro group using thionyl chloride or a
trifluoromethanesulfonate group using trifluoromethanesulfonic anhydride. The resulting
leaving group can then be displaced by a variety of nucleophiles. Sodium azide can be
used as the nucleophile to install an azide group, which can then be reduced to an amino
30 group using heterogeneous hydrogenation conditions. An amino group at the R 2 position
can be converted to an amide, sulfonamide, sulfamide, or urea using conventional
methods, such as those described in step (5) of Reaction Scheme II below. A leaving
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group at R2, such as a chloro or trifluoromethanesulfonate group, can also be displaced
with a secondary amine, a substituted phenol, or a mercaptan in the presence of a base
such as potassium carbonate. For examples of these and other methods used to install a
variety of groups at the R 2 position, see U.S. Patent No. 5,389,640 (Gerster et al). These
5 synthetic transformations may conveniently be carried out as the last steps in the synthesis.
Reaction Scheme I
Compounds of the invention, where Rib is -X-N(Rs)-Q-R4 or -X-R 5 , wherein R 5 is
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N S(0) 2 N C(O)
, or
(CH 2 ) b
(CH 2 ) a ^
A
; and A, X, Q, R, R 2a , R 3a , Rv,
R 8 , Hal, a, b, and n are as defined above, can be prepared according to Reaction Scheme
5 XIV is treated with a Boc-protected diamine of Formula (CH 3 ) 3 CO-C(0)-NH-X-NH 2 to
provide a 3-nitro[l,5]naphthyridin-4-amine of Formula XX. Several Boc-protected
diamines of Formula (CH 3 ) 3 CO-C(0)-NH-X-NH 2 are commercially available; others can
be prepared by known synthetic methods. The reaction is conveniently carried out by
adding a solution of the Boc-protected diamine of Formula (CH 3 ) 3 CO-C(0)-NH-X-NH 2 to
10 a cooled solution of the 4-chloro-3-nitro[l,5]naphthyridine of Formula XIV in a suitable
solvent, such as dichloromethane, in the presence of a tertiary amine, such as
triethylamine. The reaction can be carried out at ambient temperature. Alternatively, a
4-chloro-3-nitro[l,5]naphthyridine of Formula XIV can be combined with a diamine of
Formula NH 2 -X-NH 2 under the conditions described above, and the product can be
1 5 protected with a Boc group using conventional methods.
In steps (2) and (3) of Reaction Scheme n, a 3-nitro[l,5]naphthyridin-4-amine of
Formula XX is first reduced to provide a [l,5]naphthyridine-3,4-diamine of Formula XXI,
which is converted to li7-imidazo[4,5-c][l,5]naphthyridine of Formula XXII by reaction
with a carboxylic acid equivalent. Steps (2) and (3) of Reaction Scheme II can be carried
20 out as described for steps (6) and (7) of Reaction Scheme I.
In step (4) of Reaction Scheme II, the Boc-protecting group of a
li/-imidazo[4,5-c][l,5]naphthyridine of Formula XXII is removed to provide a 1-
aminoalkyl-liJ-imidazo[4,5-c][l,5]naphthyridine of Formula XXIII. The reaction is
conveniently carried out by adding hydrochloric acid or a solution of hydrochloric acid in
25 ethanol to a solution of a l/Z-imidazo[4,5-c][l,5]naphthyridine of Formula XXII in a
suitable solvent, such as ethanol. The reaction can be carried out at an elevated
temperature, for example, the reflux temperature of the solvent, or at ambient temperature.
In step (5) of Reaction Scheme II, a li/-imidazo[4,5-c] [ 1 ,5]naphthyridine of
Formula XXIII is converted to a l#-imidazo[4,5-c] [ 1 ,5]naphthyridine of Formula XXIV,
30 where Ri b is as defined above, using conventional methods. For example, a 1H-
II.
In step (1) of Reaction Scheme II, a4-chloro-3-nitro[l,5]naphthyridine of Formula
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imidazo[4,5-c][l,5]naphthyridine of Formula XXIII can react with an acid chloride of
Formula R4C(0)C1 to provide a compound of Formula XXIV in which Rib is
-X-N(R 8 )-Q-R4, and Q is -C(O)-. In addition, a li/-imidazo[4,5-c][l,5]naphthyridine of
Formula XXIII can react with sulfonyl chloride of Formula R4S(0)2C1 or a sulfonic
5 anhydride of Formula (R4S(0) 2 )20 to provide a compound of Formula XXIV in which Ri b
is -X-N(R 8 )-Q-R4, and Q is -S(0) 2 -. Numerous acid chlorides of Formula R4C(0)C1,
sulfonyl chlorides of Formula R4S(0)2C1, and sulfonic anhydrides of Formula (R4S(0)2)20
are commercially available; others can be readily prepared using known synthetic
methods. The reaction is conveniently carried out by adding the acid chloride of Formula
10 R4C(0)C1, sulfonyl chloride of Formula R4S(0) 2 C1, or sulfonic anhydride of Formula
(R4S(0) 2 )20 to a solution of the li/-imidazo[4,5-c][l,5]naphthyridine of Formula XXIII in
a suitable solvents such as chloroform, dichloromethane, or DMF. Optionally a base, such
as triethylamine or TV.V-diisopropylethylamine, can be added. The reaction can be carried
out at ambient temperature or a sub-ambient temperature such as 0 °C.
1 5 Ureas of Formula XXrV can be prepared by reacting a l#-imidazo[4,5-
c][l,5]naphthyridine of Formula XXIII with isocyanates of Formula R4N=C=0 or
Formula R4(CO)N=C=0, isothiocyanates of Formula R(N=C=S, sulfonyl isocyanates of
Formula R4S(0) 2 N=C=0, or carbamoyl chlorides of Formula R4N-(R 8 )-C(0)C1 or
20 others can be readily prepared using known synthetic methods. The reaction can be
carried out as described above for the reaction of a compound of Fonnula XXIII with acid
chlorides or sulfonyl chlorides to provide a compound of Formula XXIV wherein Ri b is
-X-N(R 8 )-Q-R4or
. Numerous compounds of these types are commercially available;
W
—X-N V
(CH 2 ) b ^
(CH 2 ) a ^
A
, in which Q is -C(R6)-N(R 8 )-W-, and Re, R 8 , W, A, a, and b are
25
as defined above.
Compounds of Formula XXIV where Rib is -X-R 5 and R 5 is
N — S(0) 2 N — C(O)
T or
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can be prepared by treating an amino-substituted l/f-imidazo[4,5-c][l,5]naphthyridine of
Formula XXIII with a chloroalkanesulfonyl chloride of Formula C1-R 7 S(0) 2 C1 or a
chloroalkanoyl chloride of Formula C1-R 7 C(0)C1. The reaction is conveniently carried
out by adding the chloroalkanesulfonyl chloride or chloroalkanoyl chloride to a solution of
5 the amino-substituted l#-imidazo[4,5-c] [ 1 ,5]naphthyridine of Formula XXIII in a suitable
solvent, such as chloroform, at ambient temperature. The isolable intermediate
chloroalkanesulfonamide or chloroalkanamide can then be treated with a base, such as 1,8-
diazabicyclo[5.4.0]undec-7-ene, at ambient temperature in a suitable solvent, such as
DMF, to effect the cyclization.
1 0 Sulfamides of Formula XXTV, where Ri b is -X-N(R 8 )-Q-R4, and Q is
-S(0)2-N(Rg)-, can be prepared by reacting a compound or salt of Formula XXIII with
sulfuryl chloride to generate a sizlfamoyl chloride in situ, and then reacting the sulfamoyl
chloride with an amine of formula HN(Rg)R4. Alternatively, sulfamides of Formula XXIV
can be prepared by reacting a corapound of Formula XXIII with a sulfamoyl chloride of
15 formula R4(R8)N-S(0)2C1. Many amines of Formula HN(Rg)R4, and some sulfamoyl
chlorides of Formula R4(T<8)N-S(0)2C1 are commercially available; others can be prepared
using known synthetic methods.
In steps (6) and (7) of Reaction Scheme II, a li/-imidazo[4,5-c][l,5]naphthyridine
of Formula XXIV is oxidized to afford a l//-imidazo[4,5-c][l,5]naphthyridine-5A'-oxide
20 of Formula XXV, which is animated to provide a l#-imidazo[4,5-c] [ 1 ,5]naphthyridin-4-
amine of Formula XlXa. Steps (6) and (7) of Reaction Scheme II can be carried out as
described for steps (8) and (9), respectively, of Reaction Scheme I.
hi step (8) of Reaction Scheme II, a li/-imidazo[4,5-c][l,5]naphthyridin-4-amine
of Formula XlXa undergoes a palladium-catalyzed coupling reaction to provide a 1H-
25 imidazo[4,5-c][l,5]naphthyridin-4-amine of Formula lib, which is a subgenus of Formulas
I and II. The Suzuki coupling or Heck reaction can be carried out as described in step (10)
of Reaction Scheme I.
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Compounds of the invention, wherein -Z- is ethylene, can be prepared as shown in
Reaction Scheme III, wherein Ar a , R, and n are as defined above; and R2 C and R ic include
R 2a , Ria, and Ri b groups as defined above that are not subject to reduction under the
conditions described in Reaction Scheme HI. These groups include, for example, alkenyl
and alkynyl groups.
In Reaction Scheme III, the vinyl group of a li/-imidazo[4,5-c][l,5]naphthyridin-
4-amine of Formula XXVII is reduced to provide an li/-imidazo[4,5-c][l,5]naphthyridin-
4-amine of Formula XXVIII, which is a subgenus of Formulas I and II. Compounds of
Formula XXVII can be prepared by the Suzuki coupling or the Heck reaction described in
step (10) of Reaction Scheme I. The reduction can. be carried out by hydrogenation using
a conventional heterogeneous hydrogenation catalyst, such as palladium on carbon. The
reaction can conveniently be carried out on a Parr apparatus in a suitable solvent, such as
ethanol, methanol, or mixtures thereof.
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Palladium-catalyzed coupling reactions can also be used to prepare compounds of
5 the invention according to Reaction Scheme IV, wherein Ri c , R 2c , 33-9, R, Hal, Ar a , and n
are as defined above. In step (1) of Reaction Scheme IV, a halogen-substituted IH-
imidazo[4 3 5-c][l,5]naphthyridin-4-amine of Formula XlXb undergoes a Suzuki-type
coupling with a potassium alkenyltrifluoroborate of Formula XXIX to provide a vinyl-
substituted l/f-imidazo[4,5-c][l,5]naphthyridin-4-amine of Formula XXX. The reaction
10 is conveniently carried out by combining the compound of Formula XlXb and a
compound of Formula XXIX, such as potassium vinyltrifluoroborate, in the presence of
dichloro[l,r-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct and
a base, such as triethylamine, in a suitable solvent, such as rc-propanol. The reaction can
be carried out at an elevated temperature such as the reflux temperature of the solvent
15 under an inert atmosphere.
In step (2) of Reaction Scheme IV, the Heck reaction is used to couple a vinylated
lif-imidazo[4,5-c][l,5]naphthyridin-4-amine of Formula XXX with an aryl or hetereoaryl
halide of Formula Ar a -Hal or a trifluoromethanesulfonate of Formula Ar a -OS0 2 CF 3 .
Numerous compounds of Formula Ar a -Hal are commercially available; others can be
20 prepared using known synthetic methods. The reaction is conveniently carried out under
the Heck reaction conditions described in step (10) of Reaction Sclieme I to provide a 1H-
imidazo[4,5-c][l,5]naphthyridin-4-amine of Formula XXXI, whicli is a subgenus of
Formulas I and II.
In step (3) of Reaction Scheme IV, the vinyl group of a liZ"-imidazo[4,5-
25 c][l,5]naphthyridin-4-amine of Formula XXXI is reduced to provide a l#-imidazo[4,5-
c] [ 1 ,5]naphthyridin-4-amine of Formula XXXII. The reaction is conveniently carried out
by hydrogenation under the conditions described in Reaction Scheme III.
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Reaction Scheme IV
5 Compounds of the invention can also be prepared according to Reaction Scheme
V, wherein R, R 2a , Hal, and n are as defined above; Ri d includes groups defined by R_i a and
Rib described above; and HA is a heteroaryl group attached to the ring at a nitrogen atom.
In Reaction Scheme V, a halogen-substituted li/-imidazo[4,5-c][l,5]naphthyridin-4- amine
of Formula XIXc undergoes a copper-catalyzed animation with a nitrogen-containing
1 0 heteroaryl compound to provide a l/7-imidazo[4,5-c] [ 1 ,5]naphthyridin-4-amine of
Formula XXXIII, which is a subgenus of Formulas I and II. Several nitrogen-containing
heteroaryl compounds, such as imidazole, pyrazole, and pyrrole, are commercially
available; others can be prepared by known methods. The reaction is conveniently carried
out by combining the li/-imidazo[4,5-c][l,5]naphthyridin-4-amine of Formula XIXc and
1 5 the nitrogen-containing heteroaryl compound in the presence of copper (I) iodide,
potassium phosphate, and £ra»s-l,2-diaminocyclohexane in a suitable solvent, such as 1,4-
dioxane. The reaction can be carried out at an elevated temperature, such as 1 10 °C.
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Reaction Scheme V
For some embodiments, compounds of the invention can be prepared according to
5 Reaction Scheme VI, wherein R, R ld , R 2a , M X, Hal, Z a , and n are as defined above; and
Ar b is -Ar'-X-Y-Rt or -Ar'-X-R 5 , wherein Y, R4, and R 5 are as defined above. In step (1)
of Reaction Scheme VI, a halogen-substituted l#-imidazo[4,5-c][l,5]naphthyridin-4-
amine of Formula XrXc undergoes Suzuki coupling with a boronic acid of Formula
NH 2 -X-Ar'-Z a -B(OH)2, an anhydride thereof, or a boronic acid ester of Formula
10 NH 2 -X-Ar'-Z a -B(0-alkyl) 2 to provide an l J ff-imidazo[4,5-c][l,5]naphthyridin-4-amine of
Formula XXXIV, a subgenus of Formulas I and II. The reaction can be carried out
according to one of the Suzuki coupling methods described in step (10) of Reaction
Scheme I. Some reagents of Formula NH 2 -X-Ar*-Z a -B(OH) 2 , anhydrides thereof, and
NH 2 -X-Ar'-Z a -B(0-alkyl) 2 are commercially available; others can be prepared by known
15 methods.
In step (2) of Reaction Scheme VI, a l^-imidazo[4,5-c][l,5]naphthyridine of
Formula XXXIV is converted to a l#-imidazo[4,5-c][l,5]naphthyridine of Formula
XXXV, a subgenus of Formulas I and II, using one of the methods described in step (5) of
Reaction Scheme II.
20 Reaction Scheme VI
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Some amines of the Formula H 2 N-Ri a , which are used in step (5) of Reaction
Scheme I, can be made according to the following methods. For some embodiments, Ri a
is a 1-hydroxycycloalkylmethyl group, a (4-hydroxytetrahydro-2i7-pyran-4-yl)methyl
group, or a group derived from a [l-(terf-butoxycarbonyl)-4-hydroxypiperidin-4-yl]methyl
5 group. The corresponding amines of Formula H 2 N-R] a can be prepared by combining a
cyclic ketone, such as cyclopentanone, cyclobutanone, tetrahydro-4£/-pyran-4-one, and
tert-butyl 4-oxo- 1-piperidinecarboxylate, with excess nitromethane in a suitable solvent,
such as ethanol or methanol, in the presence of a catalytic amount of base, such as sodium
ethoxide or sodium hydroxide, and reducing the resultant nitromethyl-substituted
10 compound using conventional heterogeneous hydrogenation conditions. The
hydrogenation is typically carried out in the presence of a catatlyst, such as palladium
hydroxide on carbon, palladium on carbon, or Raney nickel, in a suitable solvent, such as
ethanol. Both the reaction with nitromethane and the reduction can be carried out at room
temperature. A wide variety of cyclic ketones can be obtained from commercial sources;
1 5 others can be synthesized using known synthetic methods.
For some embodiments, Ri a is a 2-fluoro-2-methylpropyl group. The
corresponding amine of Formula H 2 N-Ri a or a salt thereof can be prepared in three steps
by (i) protecting the amino group of l-amino-2-methylpropan-2-ol with a suitable
protecting group such as a Boc group, (ii) converting the hydroxy group into a fluoro
20 group, and (iii) deprotecting the amino group. The fluorination in step (ii) can be carried
out by combining the protected amino alcohol with (diethylamino)sulfur trifluoride in a
suitable solvent, such as dichloromethane. The reaction can be carried out at or below
room temperature.
Compounds of the invention can also be prepared using variations of the synthetic
25 routes shown in Reaction Schemes I through VI. For example, position isomers of
Formula XIX such as [l,6]naphthyridines, [l,7]naphthyridines, and [l,8]naphthyridines
can be prepared according to the methods shown in Reaction Scheme I and can be used as
starting materials in Reaction Schemes III through VI. In addition, steps in Reaction
Schemes I and II may be carried out in a different order. Compounds of the invention can
30 also be prepared using the synthetic routes described in the EXAMPLES below.
Prodrugs can be prepared in a variety of ways. For example, a compound wherein
R 2 or Ri is -X-OH (e.g. hydroxyalkyl) can be converted into a prodrug wherein R 2 or Ri
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is, for example, -X-0-C(R 6 )-R4, -X-0-C(R6)-0-R4, or -X-0-C(R 6 )-N(R 8 )-R4, wherein X,
R4, R6, and Rg are as defined above, using methods known to one skilled in the art. In
addition, a compound wherein R is hydroxy may also be converted to an ester, an ether, a
carbonate, or a carbamate. For any of these compounds containing an alcohol functional
5 group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol
group with a group such as C1-6 alkanoyloxymethyl, l-(Ci_6 alkanoyloxy)ethyl, 1-methyl-
l-(Ci_6 alkanoyloxy)ethyl, Q-6 alkoxycarbonyloxymethyl, iV-(Ci_6
alkoxycarbonyl)aminomethyl, succinoyl, Ci-6alkanoyl, a-aminoCi.4 alkanoyl, arylacyl,
-P(0)(OH) 2 , -P(0)(0-Ci- 6 aIkyl) 2 , Ci- 6 alkoxycarbonyl, Ci- 6 alkylcarbamoyl, and
10 a-aminoacyl or a-aminoacyl-a-aminoacyl, where each a-aminoacyl group is
independently selected from racemic, D-, and L-amino acids. For compounds containing
an alcohol functional group, particularly useful prodrugs are esters made from carboxylic
acids containing one to six carbon atoms, unsubstituted or substituted benzoic acid esters,
or esters made from amino acids.
1 5 Prodrugs can also be made from a compound containing an amino group by
conversion of the amino group to a functional group such as an amide, carbamate, urea,
amidine, or another hydroylizable group using conventional methods. A prodrug of this
type can be made by the replacement of a hydrogen atom in an amino group, particularly
the amino group at the 4-position, with a group such as -C(0)-R', a-aminoacyl,
20 a-aminoacyl-a-aminoacyl, -C(0)-0-R*, -C(0)-N(R")-R', -C(=NY')-R*,
-CH(OH)-C(0)-OY', -CH(OCi- 4 alkyl)Y 0 , -CH 2 Y l5 or -CH(CH 3 )Yi; wherein R* and R" are
each independently Cmo alkyl, C3.7 cycloalkyl, or benzyl, each of which may be
unsubstituted or substituted by one or more substirutents selected from the group
consisting of halogen, hydroxy, nitro, cyano, carboxy, Ci-6 alkyl, C1-4 alkoxy, aryl,
25 heteroaryl, arylCi-4 alkylenyl, heteroarylCi-4 alkylenyl, haloCi-4 alkyl, haloCi.4 alkoxy,
-0-C(0)-CH 3 , -C(0)-0-CH 3 , -C(0)-NH 2 , -0-CH 2 -C(0)-NH 2 , -NH 2 , and -S(0) 2 -NH 2 ,
with the proviso that R" can also be hydrogen; each a-aminoacyl group is independently
selected from racemic, D-, and L-amino acids; Y' is hydrogen,
Ci-6 alkyl, or benzyl; Y 0 is Q-6 alkyl, carboxyCi_6 alkylenyl, aminoCi-4 alkylenyl, mono-iV-
30 Ci_6 alkylaminoCi-4 alkylenyl, or di-N,N-C\. 6 alkylaminoCi.4 alkylenyl; and Yi is mono-Af-
Ci_6 alkylamino, di-N,N-C\^ alkylamino, morpholin-4-yl, piperidin-l-yl, pyrrolidin-l-yl, or
4-Ci_4 alkylpiperazin-l-yl. For compounds contaming an amine functional group,
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particularly useful prodrugs are amides derived from carboxylic acids containing one to
ten carbon atoms, amides dervied from racemic, D-, or L-amino acids, and carbamates
containing one to ten carbon atoms.
5 Pharmaceutical Compositions and Biological Activity
Pharmaceutical compositions of the invention contain a therapeutically effective
amount of a compound or salt of the invention as described above in combination with a
pharmaceutically acceptable carrier.
The terms "a therapeutically effective amount" and "effective amount" mean an
10 amount of the compound or salt sufficient to induce a therapeutic or prophylactic effect,
such as cytokine induction, immunomodulation, antitumor activity, and/or antiviral
activity. Although the exact amount of active compound or salt used in a pharmaceutical
composition of the invention will vary according to factors known to those of skill in the
art, such as the physical and chemical nature of the compound or salt, the nature of the
1 5 carrier, and the intended dosing regimen, it is anticipated that the compositions of the
invention will contain sufficient active ingredient to provide a dose of about 100
nanograms per kilogram (ng/kg) to about 50 milligrams per kilogram (mg/kg), preferably
about 10 micrograms per kilogram (p.g/kg) to about 5 mg/kg, of the compound or salt to
the subject. A variety of dosage forms may be used, such as tablets, lozenges, capsules,
20 parenteral formulations, syrups, creams, ointments, aerosol formulations, transdermal
patches, transmucosal patches and the like.
The compounds or salts of the invention can be administered as the single
therapeutic agent in the treatment regimen, or the compounds or salts of the invention may
be administered in combination with one another or with other active agents, including
25 additional immune response modifiers, antivirals, antibiotics, antibodies, proteins,
peptides, oligonucleotides, etc.
Compounds or salts of the invention have been shown to induce, and certain
compounds or salts of the invention may inhibit, the production of certain cytokines in
experiments performed according to the tests set forth below. These results indicate that
30 the compounds or salts are useful as immune response modifiers that can modulate the
immune response in a number of different ways, rendering them useful in the treatment of
a variety of disorders.
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Cytokines whose production may be induced by the administration of compounds
or salts of the invention generally include interferon-a (IFN-a) and/or tumor necrosis
factor-a (TNF-a) as well as certain interleukins (IL). Cytokines whose biosynthesis may
be induced by compounds or salts of the invention include IFN-a, TNF-a, IL-1, IL-6, IL-
5 10 and IL-1 2, and a variety of other cytokines. Among other effects, these and other
cytokines can inhibit virus production and tumor cell growth, making the compounds or
salts useful in the treatment of viral diseases and neoplastic diseases. Accordingly, the
invention provides a method of inducing cytokine biosynthesis in an animal comprising
administering an effective amount of a compound or salt or composition of the invention
10 to the animal. The animal to which the compound or salt or composition is administered
for induction of cytokine biosynthesis may have a disease as described infra, for example
a viral disease or a neoplastic disease, and administration of the compound or salt may
provide therapeutic treatment. Alternatively, the compound or salt may be administered to
the animal prior to the animal acquiring the disease so that administration of the
1 5 compound or salt may provide a prophylactic treatment.
In addition to the ability to induce the production of cytokines, compounds or salts
of the invention can affect other aspects of the innate immune response. For example,
natural killer cell activity may be stimulated, an effect that may be due to cytokine
induction. The compounds or salts may also activate macrophages, which in turn
20 stimulate secretion of nitric oxide and the production of additional cytokines. Further, the
compounds or salts may cause proliferation and differentiation of B-lymphocytes.
Compounds or salts of the invention can also have an effect on the acquired
immune response. For example, the production of the T helper type 1 (T H 1) cytokine IFN-
y may be induced indirectly and the production of the T helper type 2 (T H 2) cytokines IL-
25 4, IL-5 and IL-1 3 may be inhibited upon administration of the compounds or salts.
Other cytokines whose production may be inhibited by the administration of
compounds or salts of the invention include tumor necrosis factor-a (TNF-a). Among
other effects, inhibition of TNF-a production can provide prophylaxis or therapeutic
treatment of TNF-a mediated diseases in animals, making the compounds or salt useful in
30 the treatment of, for example, autoimmune diseases. Accordingly, the invention provides
a method of inhibiting TNF-a biosynthesis in an animal comprising administering an
effective amount of a compound or salt or composition of the invention to the animal. The
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animal to which the compound or salt or composition is administered for inhibition of
TNF-a biosynthesis may have a disease as described infra, for example an autoimmune
disease, and administration of the compound or salt may provide therapeutic treatment.
Alternatively, the compound or salt may be administered to the animal prior to the animal
5 acquiring trie disease so that administration of the compound or salt may provide a
prophylactic treatment.
Whether for prophylaxis or therapeutic treatment of a disease, and whether for
effecting innate or acquired immunity, the compound or salt or composition may be
administered alone or in combination with one or more active components as in, for
10 example, a vaccine adjuvant. When administered with other components, the compound
or salt and other component or components may be administered separately; together but
independently such as in a solution; or together and associated with one another such as
(a) covalently linked or (b) non-covalently associated, e.g., in a colloidal suspension.
Conditions for which compounds or salts identified herein may be used as
1 5 treatments include, but are not limited to:
(a) viral diseases such as, for example, diseases resulting from infection by an
adenovirus, a herpesvirus (e.g., HSV-I, HSV-II, CMV, or VZV), a poxvirus (e.g., an
orthopoxvirus such as variola or vaccinia, or molluscum contagiosum), a picornavirus
(e.g., rhinovirus or enterovirus), an orthomyxovirus (e.g., influenzavirus), a paramyxovirus
20 (e.g., parainfluenzavirus, mumps virus, measles virus, and respiratory syncytial virus
(RSV)), a coronavirus (e.g., SARS), a papovavirus (e.g., papillomaviruses, such as those
that cause genital warts, common warts, or plantar warts), a hepadnavirus (e.g., hepatitis B
virus), a flavivirus (e.g., hepatitis C virus or Dengue virus), or a retrovirus (e.g., a
lentivirus such as HIV);
25 (b) bacterial diseases such as, for example, diseases resulting from infection by
bacteria of, for example, the genus Escherichia, Enterobacter, Salmonella, Staphylococcus,
Shigella, Listeria, Aerobacter, Helicobacter, Klebsiella, Proteus, Pseudomonas,
Streptococcals, Chlamydia, Mycoplasma, Pneumococcus, Neisseria, Clostridium, Bacillus,
Corynebacterium, Mycobacterium, Campylobacter, Vibrio, Serratia, Providencia,
30 Chromobacterium, Brucella, Yersinia, Haemophilus, or Bordetella;
(c) other infectious diseases, such chlamydia, fungal diseases including but not
limited to candidiasis, aspergillosis, histoplasmosis, cryptococcal meningitis, or parasitic
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diseases including but not limited to malaria, Pneumocystis carnii pneumonia,
leishmaniasis, cryptosporidiosis, toxoplasmosis, and trypanosome infection;
(d) neoplastic diseases, such as intraepithelial neoplasias, cervical dysplasia,
actinic keratosis, basal cell carcinoma, squamous cell carcinoma, renal cell carcinoma,
5 Kaposi's sarcoma, melanoma, leukemias including but not limited to myelogeous
leukemia, chronic lymphocytic leukemia, multiple myeloma, non-Hodgkin's lymphoma,
cutaneous T-cell lymphoma, B-cell lymphoma, and hairy cell leukemia, and other cancers;
(e) Th2 -mediated, atopic diseases, such as atopic dermatitis or eczema,
eosinophilia, asthma, allergy, allergic rhinitis, and Ommen's syndrome;
10 (f) certain autoimmune diseases such as systemic lupus erythematosus, essential
thrombocythaemia, multiple sclerosis, discoid lupus, alopecia areata; and
(g) diseases associated with wound repair such as, for example, inhibition of keloid
formation and other types of scarring (e.g., enhancing wound healing, including chronic
wounds).
1 5 Additionally, a compound or salt of the present invention may be useful as a
vaccine adjuvant for use in conjunction with any material that raises either humoral and/or
cell mediated immune response, such as, for example, live viral, bacterial, or parasitic
immunogens; inactivated viral, tumor-derived, protozoal, organism-derived, fungal, or
bacterial immunogens; toxoids; toxins; self-antigens; polysaccharides; proteins;
20 glycoproteins; peptides; cellular vaccines; DNA vaccines; autologous vaccines;
recombinant proteins; and the like, for use in connection with, for example, BCG, cholera,
plague, typhoid, hepatitis A, hepatitis B, hepatitis C, influenza A, influenza B,
parainfluenza, polio, rabies, measles, mumps, rubella, yellow fever, tetanus, diphtheria,
hemophilus influenza b, tuberculosis, meningococcal and pneumococcal vaccines,
25 adenovirus, HIV, chicken pox, cytomegalovirus, dengue, feline leukemia, fowl plague,
HSV-1 and HSV-2, hog cholera, Japanese encephalitis, respiratory syncytial virus,
rotavirus, papilloma virus, yellow fever, and Alzheimer's Disease.
Compounds or salts of the present invention may be particularly helpful in
individuals having compromised immune function. For example, compounds or salts may
30 be used for treating the opportunistic infections and tumors that occur after suppression of
cell mediated immunity in, for example, transplant patients, cancer patients and HIV
patients.
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Thus, one or more of the above diseases or types of diseases, for example, a viral
disease or a neoplastic disease may be treated in an animal in need thereof (having the
disease) by administering a therapeutically effective amount of a compound or salt of the
invention to the animal.
5 An amount of a compound or salt effective to induce or inhibit cytokine
biosynthesis is an amount sufficient to cause one or more cell types, such as monocytes,
macrophages, dendritic cells and B-cells to produce an amount of one or more cytokines
such as, for example, IFN-a, TNF-a, IL-1, EL-6, IL-10 and IL-12 that is increased
(induced) or decreased (inhibited) over a background level of such cytokines. The precise
10 amount will vary according to factors known in the art but is expected to be a dose of
about 100 ng/kg to about 50 mg/kg, preferably about 10 ug/kg to about 5 mg/kg. The
invention also provides a method of treating a viral infection in an animal and a method of
treating a neoplastic disease in an animal comprising administering an effective amount of
a compound or salt or composition of the invention to the animal. An amount effective to
15 treat or inhibit a viral infection is an amount that will cause a reduction in one or more of
the manifestations of viral infection, such as viral lesions, viral load, rate of virus
production, and mortality as compared to untreated control animals. The precise amount
that is effective for such treatment will vary according to factors known in the art but is
expected to be a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 ug/kg to
20 about 5 mg/kg. An amount of a compound or salt effective to treat a neoplastic condition
is an amount that will cause a reduction in tumor size or in the number of tumor foci.
Again, the precise amount will vary according to factors known in the art but is expected
to be a dose of about 100 ng/kg to about 50 rng/kg, preferably about 10 ug/kg to about 5
mg/kg.
25 In addition to the formulations and uses described specifically herein, other
formulations, uses, and administration devices suitable for compounds of the present
invention are described in, for example, International Publication Nos. WO 03/077944 and
WO 02/036592, U.S. Patent No. 6,245,776, and U.S. Publication Nos. 2003/0139364,
2003/185835, 2004/0258698, 2004/0265351, 2004/076633, and 2005/0009858.
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EXAMPLES
Objects and advantages of this invention are further illustrated by the following
examples, but the particular materials and amounts thereof recited in these examples, as well
as other conditions and details, should not be construed to unduly limit this invention.
In the examples below automated flash chromatography was carried out using a
HORIZON HPFC system (an automated high-performance flash purification product
available from Biotage, Inc, Charlottesville, Virginia, USA). For some of these
purifications, either a FLASH 40+M silica cartridge or a FLASH 651 silica cartridge (both
available from Biotage, Inc, Charlottesville, Virginia, USA) was used. The eluent used for
each purification is given in the example. In some chromatographic separations, the
solvent mixture 80/18/2 v/v/v chloroform/methanol/concentrated ammonium hydroxide
(CMA) was used as the polar component of the eluent. In these separations, CMA was
mixed with chloroform in the indicated ratio.
Preparation of 5-(te/^-Butyldimethylsilanyloxymethyl)pyridine-3-boronic acid
3-Bromo-5-(te^butyldimethylsilanyloxymethyl)pyridiiie was prepared according
to the published procedure (Zhang, N. et al, J. Med. Chem., 45 9 2832-2840 (2002)). Under
a nitrogen atmosphere, a solution of 3-bromo-5-(tert-
butyldimethylsilanyloxymethyl)pyridine (28.70 g, 94.94 mmol) and triisopropyl borate
(26.3 mL, 1 14 mmol) in dry tetrahydrofuran was cooled to -70 °C. w-Butyllithium (45.6
mL, 114 mmol) was added dropwise over a period of 1 .5 hours. The reaction was stirred
for an additional 30 minutes and then allowed to warm to -20 °C. Dilute aqueous
ammonium chloride was added, and the mixture was allowed to warm to ambient
temperature. The aqueous layer was separated and extracted with diethyl ether. The
combined organic fractions were concentrated under reduced pressure, and methanol was
added to the resulting oil. A solid formed, which was stirred with water for two days,
isolated by filtration, and dried under reduced pressure to provide 18.19 g of 5-(tert-
butyldimethylsilanyloxymethyl)pyridine-3-boronic acid as a white solid.
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Example 1
2-(Ethoxymethyl)4-(2-methylpropyl)-7-(pyridin-3-yl)-lF-imidazo[4,5-
c] [ 1 ,5]naphthyridin-4- amine
Part A
A mixture of triethyl orthoformate (10 mL, 60.1 mmol) and 2,2-dimethyT-[l,3]-
dioxane-4,6-dione (40.9 g, 0.23 mol) (Meldrum's acid) was heated at 92 °C for 90 minutes
and then cooled to 70 °C over one hour. 3-Amino-5-bromopyridine (40.9 g, 0.20 mol)
was slowly added over 10 minutes with an ethanol rinse while maintaining the reaction
temperature between 60 and 70 °C. The reaction was then heated for an additional 20
minutes and allowed to cool to room temperature. The reaction mixture was filtered and
washed with ethanol (150 mL) yielding a tan solid. The solid was dried under vacuum for
2 hours to yield 59.14 g of 5-{[(5-bromopyridin-3-yl)imino]methyl}-2,2-dimethiyl-l,3-
dioxane-4,6-dione as a light yellow crystalline solid, mp 200-202 °C.
l R NMR (300 MHz, CDC1 3 ) 5 1 1.26 (d, J= 14.3 Hz, 1H), 8.80 (d, J= 2.3 Hz, 1 H), 8.62
(d, 14.3 Hz, 1H), 8.56(d, J= 1.9 Hz, 1H), 8.44-8.40 (m, 1H), 1.68 (s, 6H).
PartB
5- {[(5-Bromopyridin-3-yl)imino]methyl} -2,2-dimethyl-l ,3-dioxane-4,6-dione (59
g, 0. 1 8 mol) was slowly added to DOWTHERM A heat transfer fluid (2000 mL) over a
period of 5 minutes at 235-238 °C. Following addition, the reaction was maintained for an
additional 5 minutes and then allowed to cool to 40 °C. A brown precipitate formed,
which was filtered and washed with hexanes (150 mL). The brown solid was suspended
in an ethanol/water mixture (90: 10, 1500 mL), heated to a boil for 30 minutes, isolated by
filtration, and washed with ethanol (200 mL) to yield 30.8 g of 7-bromo[l,5]naphthyridin-
4-ol as a dark brown powder.
l R NMR (300 MHz, CDC1 3 ) 8 11.81(brs, 1H), 8.69(d, J= 1.9 Hz, 1H), 8.21 (d, J= 1.9
Hz, 1H), 7.95(d, J= 7.7 Hz, 1H), 6.22 (d, J= 7.5 Hz, 1H).
PartC
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A mixture of 7-bromo[l,5]naphthyridin-4-ol (33 g, 0.147 mol) and fuming nitric
acid (350 mL) was heated at reflux (90 °C internal reaction vessel temperature) for 3
hours. The reaction mixture was cooled to 50 °C, poured over 1 L of ice and neutralized
to pH 2-3 with a solution of 50% aqueous NaOH. The resulting precipitate was filtered,
5 washed with water, and dried over vacuum for 3 days to yield 25.1 g of 7-bromo-3-
nitro[l,5]naphthyridin-4-ol as a yellow crystalline solid.
! H NMR (300 MHz, CDC1 3 ) 5 13.06(br s, 1H), 9.26(s, 1H), 8.88 (d, /= 2.0 Hz, 1H),
8.37(d,/=2.0Hz, 1H).
PartD
10 Phosphorous oxychloride (16.76 g, 10.19 mL, 109.3 mmol) was added slowly
dropwise to a suspension of 7-bromo-3-nitro[l,5]naphthyridin-4-ol (21.09 g, 78.1 mmol)
in 7Y,/Y-dimethylfonnamide (250 mL) (DMF) at ambient temperature and maintained
overnight. The reaction mixture was then added to ice water (400 mL) with stirring. A
solid precipitate formed, which was isolated by vacuum filtration and washed with water.
1 5 The material was dried under high vacuum at ambient temperature overnight to yield
20.79 g of 7-bromo-4-chloro-3-nitro[l,5]naphthyridine as a tan solid.
! H NMR (300 MHz, CDC1 3 ) 8 9.51(s, 1H), 9.36 (d, J= 2.2 Hz, 1H), 9.02(d, J= 2.1
Hz,lH).
PartE
20 Triethylamine (17.97 mL, 129.0 mmol) was added to a solution of 7-bromo-4-
chloro-3-nitro[l,5]naphthyridine (24.8 g, 86.0 mmol) in dichloromethane (200 mL) at 0
°C. Isobutylamine (9.40 mL, 94.6 mmol) was added dropwise to the mixture, and the
mixture was stirred for 3 hours at ambient temperature. The reaction mixture was
condensed under reduced pressure to a solid, which was triturated with water (200 mL).
25 The precipitate was filtered, washed sequentially with water and hexanes, and dried to
yield 27.5 g of 7-bromo-3-nitro[l,5]naphthyridin-4-yl-(2-methylpropyl)amine as a yellow
powder, mp 114-115 °C.
*H NMR (300 MHz, CDC1 3 ) 8 9.98(br s, 1H), 9.37(br s, 1H), 8.81 (d, J= 2.2 Hz, 1H),
8.39(d, J= 2.2 Hz, 1H), 4.36-4.01(br m, 2H), 2.06(heptet, J= 6.7 Hz, 1H), 1.09(d, J= 6.7,
30 6H). MS (APCI) m/z 325.2 and 327.2 (M+H) + ;
Anal, calcd for C 12 H 13 BrN40 2 : C, 44.33; H, 4.03; N, 17.23. Found: C, 44.32; H, 3.81; N,
17.33.
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PartF
A solution of sodium dithionite (77.95 g, 380.6 mmol) and potassium carbonate
(58.35 g, 422.2 mmol) in water (250 mL) was added dropwise to a mechanically stirred
solution of 7-bromo-3-nitro[l,5]naphthyridin-4-yl-(2-methylpropyl)amine (27.6 g, 84.6
5 mmol) and ethyl viologen dibromide (0.63 g, 1.7 mmol) in dichloromethane (300 mL) and
water (50 mL). The reaction mixture was stirred overnight at ambient temperature. Water
(500 mL) was added, and the reaction mixture was stirred for 10 minutes. The organic
layer was separated and the aqueous layer was filtered through WHATMAN paper to
remove insoluble material. The emulsion-free filtrate was extracted with
10 dichloromethane, washed sequentially with water and brine, dried over sodium sulfate,
filtered, and concentrated under reduced pressure to yield 22.3 g of 7-bromo-iV 4 -(2-
methylpropyl)[l,5]naphthyridine-3,4-diamine as an orange solid.
! H NMR (300 MHz, CDC1 3 ) 8 8.70 (d, J= 2.2 Hz, 1H), 8.36(s, 1H), 8.33(d, J= 2.2 Hz,
1H), 6.03-5.89(br m, 1H), 3.66(br s, 2H), 3.27(t, /= 6.8, 2H), 1.83(heptet, J= 6.7 Hz,
15 1H), 1.00(d,J=6.7Hz,6H). ,.
Part G i :
A solution of 7-bromo-A^-(2-methylpropyl)[l,5]naphthyridine-3,4-diamine (22.29
g, 75.51 mmol) in dichloromethane (300 mL) was cooled to 0 °C, and triethylamine (13.15
mL, 94.39 mmol) was added to the reaction mixture. Ethoxyacetyl chloride (1 1 .56 g,
20 94.39 mmol) was added dropwise to the reaction mixture, and the reaction was maintained
at ambient temperature for 2.5 hours. The reaction mixture was concentrated under
reduced pressure, triethylamine (52.62 mL, 377.6 mmol) and ethanol (250 mL) was added,
and the resulting mixture was heated at reflux for 16 hours. The solvent was removed
under reduced pressure and the residue was triturated with n-heptanes. The resulting
25 precipitate was collected by filtration, washed with water, and dried. The product was
then recrystallized from acetonitrile to yield 14 g of 7-bromo-2-(ethoxymethyl)-l-(2-
methylpropyl)-l//-imidazo[4,5-c][l,5]naphthyridine as an off-white solid. The mother
liquor was concentrated, and the residue was recrystallized from acetonitrile to yield an
additional 2.37 g of 7-bromo-2-(ethoxymethyl)-l-(2-methylpropyl)-li7-imidazo[4,5-
30 c] [ 1 ,5]naphthyridine. The n-heptanes fraction from the trituration was concentrated under
reduced pressure, triturated with acetonitrile, and isolated by filtration to give an
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additional 0.88 g of 7-bromo-2-(ethoxymethyl)-l-(2-methylpropyl)-l//-imidazo[4,5-
e][l,5]naphthyridine, for a total yield of 17.25 g of an off-white solid, mp 115-1 16 °C.
] H NMR (300 MHz, CDC1 3 ) § 9.33(s, 1H), 8.96(d, J= 2.2 Hz, 1H), 8.68(d, J= 2.2 Hz,
1H), 4.90(s, 2H), 4.78(d, J= 7.6 Hz, 2H), 3.64(q, J= 7.0 Hz, 2H), 2.47(heptet, J= 6.9 Hz,
5 1H), 1.26(t, /= 7.0, 3H), 0.98(d, J= 7.0 Hz, 6H). 13 C NMR (75 MHz, CDC1 3 ) 5 152.6,
149.7, 147.2, 140.3, 139.3, 139.1, 134.5, 133.9, 117.9, 66.5, 65.3, 53.2, 29.7, 19.8, 15.0.
MS (APCI) m/z 363.2 and 365.2 (M+H) + ;
Anal, calcd for Ci 6 Hi 9 BrN 4 0: C, 52.90; H, 5.27; N, 15.42. Found: C, 52.93; H, 5.22; N,
15.55.
10 PartH
3-Chloroperoxybenzoic acid (77% pure, 17.1 1 g, 76.36 mmol) (mCPBA) was
added to a stirred solution of 7-bromo-2-(ethoxymethyl)-l-(2-methylpropyl)-lii/-
imidazo[4,5-c][l,5]naphthyridine (13.87 g, 38.18 mmol) in dichloromethane (275 mL),
and the reaction was stirred for 2 hours with additional mCPBA (2.91 g, 13.0 mmol)
15 added after 1 hour. Ammonium hydroxide (90 mL) was added followed by addition of p-
toluenesulfonyl chloride (9.10 g, 47.73 mmol) in small portions at 0 °C; the reaction was
then allowed to warm to ambient temperature for 4 hours. The reaction mixture was
filtered and then diluted with dichloromethane (300 mL) and a 4% solution of sodium
carbonate (200 mL). The organic layer was separated and the aqueous layer was extracted
20 with dichloromethane (2 x 100 mL). The combined organic fractions were dried over
sodium sulfate, filtered, and concentrated under reduced pressure to produce an orange
solid. The crude product was triturated with acetonitrile to yield 8.4 g of a tan solid,
which upon purification by automated flash chromatography (using a silica gel cartridge,
eluting with chloroform:CMA, ranging in ratios from 100:0 to 80:20) to provide 7.03 g of
25 7-bromo-2-(ethoxymethyl)-l-(2-methylpropyl)-li^-imidazo[4,5-c][l,5]naphthyridin-4-
amine as an off-white solid, mp 163-164 °C.
'H-NMR (300 MHz, DMSO) 5 8.57(d, J= 2.2 Hz, 1H), 8.10(d, /= 2.2 Hz, 1H), 7.15(br s,
2H), 4.77(s, 2H), 4.64(d, J= 7.6 Hz, 2H), 3.60(q, /= 7.0 Hz, 2H), 2.43-2.28(m, 1H),
1.16(t, J= 7.0, 3H), 0.89(d, J =6.7 Hz, 6H). MS (APCI) m/z 378.2 and 380.2 (M+H) + .
30 Anal, calcd for Ci 6 H 2 oBrN 5 0: C, 50.80; H, 5.33; N, 18.51. Found: C, 50.62; H, 5.30; N,
18.52.
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Parti
Pyridine-3-boronic acid (0.39 g, 3.2 mmol) was added to 7-bromo-2-
(ethoxymethyl)-l-(2-methylpropyl)-l//-imidazo[4,5-c][l,5]naphthyridin-4-am (1.0 g,
2.6 mmol) and 1-propanol (17 mL). The mixture was degassed and backfilled with
5 nitrogen. Aqueous 2M sodium carbonate (1.6 mL), water (2 mL), triphenylphosphine
(.021 g, 0.079 mmol), and palladium (II) acetate (0.0058 g, 0.026 mmol) were added to the
reaction mixture followed by subsequent degassing. The mixture became homogenous
upon heating at reflux for 1 hour. After an additional 1 hour of heating, the reaction was
cooled to ambient temperature and extracted into chloroform. The resulting solution was
10 washed with saturated aqueous sodium chloride solution, dried over sodium sulfate,
filtered and concentrated under reduced pressure. The crude product was purified by
automated flash chromatography (using a silica gel cartridge, eluting with
CMAxhloroform ranging in ratios from 0: 100 to 30:70) and concentrated under reduced
pressure. The product was recrystallized from acetomtrile, filtered, and dried at 60 °C
1 5 under vacuum to provide 0.66 g of 2-(ethoxymethyl)-l -(2-methylpropyl)-7-(pyridin-3-yl)-
l/Z-imidazo[4,5-c][l,5]naphthyridin-4-amine as a white solid, mp 177-179 °C.
! H NMR (300 MHz, DMSO) 5 9.07(m, 1H), 8.91(d, /= 2.2 Hz, 1H), 8.64(dd, J= 4.8, 1.6
Hz, 1H), 8.31-8.25(m, 1H), 8.22(d, J= 2.2 Hz, 1H), 7.58-7.51(m, 1H). 7.03 (br s, 2H),
4.80(s, 2H), 4.72(d, J= 7.6 Hz, 2H), 3.60(q, /= 7.0 Hz, 2H), 2.51-2.40(m, 1H), 1.1 8(t, J=
20 7.0 Hz, 3H), 0.92(d, J= 6.7 Hz, 6H). 13 C NMR (75 MHz, DMSO) 5 152.6, 150.1, 148.8,
147.8, 141.2, 140.2, 134.4, 133.2, 132.9, 132.5, 130.9, 129.9, 128.9, 123.9, 65.4, 63.9,
51.9, 29.1, 19.3, 14.8. MS (APCI) m/z 377.1 (M+H) + ;
Anal, calcd for C 2 iH 2 4N 6 0: C, 67.00; H, 6.43; N, 22.32. Found: C, 66.82; H, 6.20; N,
22.36.
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Example 2
2-(Ethoxymethyl)- 1 -(2-methylpropyl)-7-[3-(morpholin-4-ylcarbonyl)phenyl]- IH-
imidazo[4,5-c] [ 1 ,5]naphthyridin-4-amine
5 The general method of Part I of Example 1 was followed using 3-(morpholine-4-
carbonyl)phenylboronic acid (0.745 g, 3.17 mmol) in lieu of pyridine-3-boronic acid. The
crude reaction was purified automated flash chromatography (using a silica gel cartridge,
eluting with CMAxhloroform ranging in ratios from 0:100 to 25:75). The combined clean
fractions were concentrated under reduced pressure, recrystallized from acetonitrile,
1 0 filtered, washed with acetonitrile and dried at 60 °C under vacuum to give 0.63 g of 2-
(ethoxymethyl)-l-(2-methylpropyl)-7-[3-(morpholin-4-ylcarbonyl)phenyl]-l//-
imidazo[4,5-c][l,5]naphthyridin-4-amine as a white solid, mp 185-187 °C.
*H NMR (300 MHz, DMSO) 8 8.88(d, J= 2.2 Hz, 1H), 8.16(d, 2.2 Hz, 1H), 7.97-
7.91(m, 1H), 7.89-7.84(m, 1H), 7.61(t, J= 7.7 Hz, 1H), 7.49-7.43(m, 1H). 6.98(br s, 2H),
15 4.79(s, 2H), 4.72(d, J= 7.5 Hz, 2H), 3.77-3.36(br abs, 8H), 3.60(q, J= 7.0 Hz, 2H), 2.50-
2.38(m, 1H), 1.17(t, J= 7.0 Hz, 3H), 0.93(d, J= 6.7 Hz, 6H). 13 C NMR (75 MHz,
DMSO) 5 168.6, 152.6, 150.0, 141.4, 140.3, 137.4, 136.5, 133.1, 133.0, 132.5, 129.8,
129.3, 128.8, 128.0, 126.4, 125.2, 65.9, 65.4, 63.9, 51.9, 47.7, 29.1, 19.3, 14.8. MS
(APCI) m/z 489.2 (M+H) + ;
20 Anal, calcd for C 2 7H32N 6 0 3 : C, 66.37; H, 6.60; N, 17.20. Found: C, 66.20; H, 6.68; N,
17.40.
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Example 3
2-(Ethoxymethyl)-7-(iim^
c] [ 1 ,5]naphthyridin-4-amine
NH 2
Copper (I) iodide (0.06g, 0.53 mmol), potassium phosphate (1.18 g, 5.56 mmol),
and imidazole (0.22 g, 3.17 mmol) were added to a glass tube. Sequential addition of 7-
bromo-2-(ethoxymethyl)- 1 -(2-methylpropyl)- l#-imidazo[4,5-c] [ 1 ,5]naphthyridin-4-
amine (1.0 g, 2.64 mmol), £raws-l,2-diarninocyclohexane (0.06 g, 0.53 mmol) and dioxane
(9 mL) followed. The tube was flushed with nitrogen, sealed, and heated to 1 10 °C, and
the reaction mixture was stirred for 10 days. The reaction mixture was then diluted with a
1:1 mixture of chloroform and methanol (50 mL) and filtered through CELITE filter aid.
The filtrate was concentrated under reduced pressure to give a black liquid, which was
purified by automated flash chromatography (using a silica gel cartridge, eluting with
CMA:chloroform ranging in ratios from 0:100 to 20:80), and concentrated under reduced
pressure. The residue was recrystallized from diethyl ether to give 0.18 g of 2-
(ethoxymethyl)-7-(imidazol- 1 -yl)-l -(2-methylpropyl)- lf/-imidazo[4,5-
c][l,5]naphthyridin-4-amine as a tan solid, mp 175-176 °C.
X H NMR (300 MHz, CDC1 3 ) 5 8.72 (d, J= 2.4 Hz, 1H), 8.02 (d, J= 2.4 Hz, 2H), 7.478-
7.281 (m, 2H), 5.75 (br s, 2H), 4.84 (s, 2H), 4.74 (d, J= 7.6 Hz, 2H), 3.65 (q, J= 7.0 Hz,
2H), 2.559-2.407 (m, 1H), 1.27 (t, J= 7.0 Hz, 3H), 1.00 (d, 7= 6.7 Hz, 6H). 13 C NMR (75
MHz, CDC1 3 ) 5153.0, 151.1, 141.5, 137.5, 134.2, 134.0, 132.7, 131.5, 124.9, 77.8, 77.4,
76.9, 66.9, 65.4, 53.4, 30.2, 20.2, 15.4. MS (ESI) m/z 366.3 (M+H) + ;
Anal, calcd for C19H23N7O: C, 62.45; H, 6.34; N, 26.83. Found: C, 62.16; H, 6.20; N,
27.06.
Examples 4-58
The compounds in the table below were prepared according to the following
method. A solution of 7-bromo-2-(ethoxymethyl)-l-(2-methylpropyl)-li7-imidazo[4,5-
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c][l,5]naphthyridin-4-amine (21.8 mg, 0.10 mmol) in 7:3 volume:volume (v:v)
dichloromethane:methanol (2 mL) was added to a test tube, and the solvent was removed
by vacuum centrifugation. The boronic acid (0.1 1 mmol) indicated in the table below and
?i-propanol (1.6 mL) were sequentially added, and the test tube was purged with nitrogen.
The reaction mixture was sonicated until it had the consistency of milk. Palladium (II)
acetate (0.292 mL of a 0.9 mol% solution in toluene, 0.0026 mmol), 2M aqueous sodium
carbonate solution (600 uL), deionized water (113 uL), and a solution of 0.15 mol%
triphenylphosphine in /j-propanol (52 uL, 0.00.78 mmol) were sequentially added. The
test tube was purged with nitrogen, capped, and then heated to 80 °C overnight in a sand
bath. For Example 1 1, the solvent was removed by vacuum centrifugation, and glacial
acetic acid (3 mL), tetrahydrofuran (1 mL), and deionized water (1 mL) were added to the
test tube. The reaction was heated for six hours at 60 °C.
The contents of each test tube were passed through a Waters Oasis Sample
Extractions Cartridge MCX (6 cc) according to the following procedure. Hydrochloric
acid (3 mL of 1 N in methanol) was added to adjust each example to pH 5-7, and the
resulting solution was passed through the cartridge optionally using light nitrogen
pressure. The cartridge was washed with methanol (5 mL) optionally using light nitrogen
pressure and transferred to a clean test tube. A solution of 1% ammonia in methanol (2 x
5 mL) was then passed through the cartridge optionally using light nitrogen pressure, and
the basic solution was collected and concentrated.
The compounds were purified by reversed phase preparative high-performance
liquid chromatography (prep HPLC) using a Waters Fraction Lynx automated purification
system. The prep HPLC fractions were analyzed using a Micromass LC/TOF-MS, and the
appropriate fractions were centrifuge evaporated to provide the trifluoroacetate salt of the
desired compound. Column: Zorbax BonusRP, 21.2 x 50 millimeters (mm), 5 micron
particle size; non-linear gradient elution from 5-95% B where A is 0.05% trifluoroacetic
acid/water and B is 0.05% trifluoroacetic acid/acetonitrile; fraction collection by mass-
selective triggering. The table below shows the reagent used for each example, the
structure of the resulting compound, and the observed accurate mass for the isolated
trifluoroacetate salt.
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Examples 4-58
NH
l '2 CH 3
1 1 \ CH,
CH 3
Example
Boronic acid
R
Measured
Mass
(M+H)
4
Phenylboronic acid
376.2146
5
Pyridine- 3 -boronic acid
Cf
N
377.2119
6
Pyridine— 4-boronic acid
377.2121
7
Thiophene-2-boronic acid
cr
382.1711
8
Thiophene-3 -boronic acid
cr
382.1700
9
3-Methylph.enylboronic acid
CH 3
390.2309
10
4-Methylph.enylboronic acid
390.2287
11
5-(ter?-butyldimethylsilanyloxy-
methyl)pyridine-3-boronic acid
cr
HO
407.2219
12
3-Aminophenylboronic acid
monohydrate
qr
NH 2
391.2284
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13
2-Chlorophenylboronic acid
a
410.1754
14
3-(iV,Af-Dimethylamino-
carbonyl)phenylboronic acid
Cf
V
H 3 C N A 0
CH 3
447.2524
15
o-Tolylboronic acid
CH 3
390.2317
16
4-Vinylphenylboronic acid
402.2272
17
4-Ethylphenylboronic acid
404.2445
18
3,5-Dimethylphenylboronic acid
h 3 c Y^ / '
y ~" '3
404.2451
19
Phenethylboronic acid
404.2451
20
2-Methoxyphenylboronic acid
H 3 C 0
&
406.2242
21
(4-Fluoro-2-
hydroxy)phenylboronic acid
OH
410.1995
22
2,4-Difluorophenylboronic acid
F
412.1924
23
Benzo[B]furan-2-boronic acid
416.2080
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24
4-Acetylphenylboronic acid
CH 3
418.2242
25
3-Acetylphenylboronic acid
•ij
418.2247
26
3,4-
Methylenedioxyphenylboronic
acid
OCT
420.2025
27
3-Ethoxyphenylboronic acid
420.2388
28
3-Aminophenylboronic acid
hydrochloride
391.2283
29
(2-Acetylaminophenyl)boronic
acid
o
JJ
433.2321
30
2-Ethoxy-5-
methylphenylboronic acid
CH 3
434.2340
31
2-Isopropoxyphenylboronic acid
434.2542
32
2,4-Dimethoxyphenylboronic
acid
H 3 C 0
H 3 C 0 XX
436.2352
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33
3,4-Dichlorophenylboronic acid
CI XX
444.1331
34
4-(2-
Carboxyvinyl)phenylboronic
acid
OH
446.2193
35
3-(4-Boronophenyl)propionic
acid
OH
448.2319
36
4-(Methoxycarbonyl-
amino)phenylboronic acid
H 3 c 0 A N lT
H
449.2280
37
4-(0-
Methylhydroxylaminocarbonyl)-
phenylboronic acid
H fY
0
449.2285
38
[4-(£-3-Methoxy-3-oxo-l-
propen-l-yl)phenyl]boronic acid
0
460.2364
39
3-(iV-Isopropylamino-
carbonyl)phenylboronic acid
CH 3 0
461.2662
40
4-Borono-Z)Z-phenylalanine
NH 2 f^Y
OH
463.2442
41
3,4,5-Trimethoxyphenylboronic
acid
?H 3
°CH 3
466.2456
42
4-(Ethylsulfonyl)phenylboronic
acid
°J
H 3 C
468.2053
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43
3-(2-Cyanoethylamino-
carbonyl)phenylboronic acid
472.2439
44
3-(Butylamino-
carbonyl)phenylboronic acid
0
H || 1
475.2809
45
3-(Isobutylamino-
carbonyl)phenylboronic acid
O
475.2811
46
4-(Isobutylamino-
carbonyl)phenylboronic acid
CH 3 H f|
0
475.2798
47
3-(Piperidine-l-
carbonyl)phenylboronic acid
487.2775
48
3-(Morpholine-4-
carbonyl)phenylboronic acid
oV
489.2620
49
4-(Morpholine-4-
carbonyl)phenylboronic acid
ever
0
489.2597
50
3-(Furfiirylamino-
carbonyl)phenylboronic acid
499.2435
51
4-Benzyloxy-3-
fluorophenylboronic acid
500.2449
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52
4-(4-Oxopiperidine- 1 -
carbonyl)phenylboronic acid
0
501.2581
53
3-(7\T-Benzylamino-
carbonyl)phenylboronic acid
0
509.2629
54
(4-Aminomethyl-phenyl)boronic
acid, pinacol ester hydrochloride
ft
405.2411
55
3-Cyanophenylboronic acid
III
N
401.2065
56
4-Methoxyphenylboronic acid
CH 3
406.2264
57
4-Isopropoxyphenylboronic acid
H 3 C^CH 3
434.2543
58
(3-Aminomethyl-phenyl)boronic
acid hydrochloride
H 2 N
405.2431
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Preparation of l-[4-Amino-7-bromo-2-(ethoxymethyl)-li^-imidazo[4,5-
c] [ 1 ,5]naphthyridin-l -yl]-2-methylpropan-2-ol
Part A
5 A mixture of 7-bromo-4-chloro-3-nitro[l,5]naphthyridine (92.5 g, 321 mmol) and
dichloromethane (1.5 L) was cooled to 10 °C. l-Amino-2-methylpropan-2-ol (63.01 g,
707 mmol) was added dropwise over a period of 30 minutes; during the addition, the
reaction temperature did not rise above 13 °C. The reaction mixture was allowed to warm
to room temperature slowly and stirred overnight. The solvent was removed under
10 reduced pressure, and the solid residue was mixed with deionized water (200 mL). The
solid was isolated by filtration, washed with deionized water (2 x 200 mL), and dried in a
vacuum oven overnight at 35 °C to provide l-[(7-bromo-3-nitro[l,5]naphthyridin-4-
yl)amino] -2-methylpropan-2-ol.
PartB
1 5 The material from Part A was added to a Parr vessel followed by methanol (1.13
L) and acetonitrile (2.26 L). The vessel was purged with nitrogen, and 5% platinum on
carbon (3.4 g), which had been wet with acetonitrile, was added. The reaction mixture
was placed under hydrogen pressure (50 psi, 3.4 x 10 5 Pa) overnight and filtered. The
filtrate was concentrated under reduced pressure to provide 103 g of l-[(3-amino-7-
20 bromofl ,5]naphthyridin-4-yl)amino]-2-methylpropan-2-ol as a yellow solid.
PartC
A mixture of l-[(3-amino-7-bromo[l,5]naphthyridin-4-yl)amino]-2-methylpropan-
2-ol (100.0 g, 321.4 mmol) and acetonitrile (1 L) was stirred for five minutes and
ethoxyacetyl chloride (43.3 g, 353.3 mmol) was added. The reaction was stirred overnight
25 at room temperature. The solid product was isolated by filtration and washed with
acetonitrile (200 mL) to provide 113 g of iV-{7-bromo-4-[(2-hydroxy-2-
methylpropyl)amino] [ 1 ,5]naphthyridin-3-yl} -2-ethoxyacetamide hydrochloride as a
yellow solid.
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PartD
Potassium carbonate (1 13 g) and deionized water (565 mL) were sequentially
added to a solution of A^-{7-bromo-4-[(2-hydroxy-2-
methylpropyl)amino][l,5]naphthyridin-3-yl}-2-ethoxyacetamide hydrochloride (113 g,
261 mmol) in denatured ethanol (1.695 L), and the resulting mixture was heated at reflux
(77 °C) overnight and allowed to cool to room temperature. The ethanol was removed
under reduced pressure, and the resulting mixture was filtered to isolate a solid. The solid
was washed with deionized water (100 mL) and dried over two nights in a vacuum oven at
40 °C to provide 90 g of l-[7-bromo-2-(ethoxymethyl)-lJy r -imidazo[4,5-
c][l,5]naphthyridin-l-yl]-2-methylpropan-2-ol as a brown solid. Material from a separate
run was used in the next step.
PartE
mCPBA (35.5 g of 77% purity, 158 mmol) was added to a stirred solution of l-[7-
bromo-2-(ethoxymethyl)- l#-imidazo[4,5-c] [ 1 ,5]naphthyridin- 1 -yl]-2-methylpropan-2-ol
(15 g, 0.040 mol) in chloroform (400 mL), and the reaction was stirred at room
temperature for 2.5 hours. Concentrated ammonium hydroxide (200 mL) was added, and
then ^-toluenesulfonyl chloride (18.9 g, 98.9 mmol) was added over a period of five
minutes. The reaction mixture was stirred at room temperature for 2.5 hours, and an
analysis by liquid chromatography/mass spectrometry (LC/MS) indicated the presence of
starting material. Additional /?-toluenesulfonyl chloride (11 g) was added, and the reaction
mixture was stirred at room temperature for one hour. An analysis by LC/MS indicated
the reaction was still incomplete. Additional ammonium hydroxide (100 mL) andp-
toluenesulfonyl chloride (10 g) were added, and the mixture was stirred for 30 minutes at
room temperature. The aqueous layer was separated and extracted with dichloromethane
(2 x 300 mL). The combined organic fractions were dried over magnesium sulfate,
filtered, and concentrated under reduced pressure. The residue (41.4 g) was purified by
automated flash chromatography (FLASH 651 cartridge, eluting with ethyl
acetate:methanol in a gradient from 97:3 to 85:15) to provide 5.96 g of l-[4-amino-7-
bromo-2<ethoxymethyl)4^midazo[4,5-c][l,5]naphthyridin-l-yl]-2-methylpropan-2-ol
as a yellow solid.
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Example 59
1 - [4-Amino-7-(3 ,4-difluorophenyl)-2-(ethoxymethyl)- 1 i^-imidazo [4,5-
c] [ 1 ,5]naphthyridin- 1 -yl]-2-methylpropan-2-ol
5 A suspension of l-[4-amino-7-bromo-2-(ethoxymethyl)-liJ-imidazo[4,5-
c][l,5]naphthyridin-l-yl]-2-methylpropan-2-ol (1.4 g, 3.55 mmol), 3,4-
difluorophenylboronic acid (1.12 g, 7.10 mmol), potassium carbonate (1.62 g, 11.7 mmol),
1,2-dimethyoxyethane (DME) (13 mL), and water (7 mL) was stirred under nitrogen.
Dichlorobis(triphenylphosphine)palladium(II) (0.025 g, 0.036 mmol) was added, and the
10 suspension was heated at reflux for five hours, allowed to cool to room temperature,
diluted with water (20 mL), and extracted with dichloromethane (50 mL). An emulson
formed. Solid sodium chloride was added to saturate the aqueous layer. The organic layer
was then removed under reduced pressure. The aqueous layer was extracted with
dichloromethane (4 x 50 mL); the third extraction was allowed to stand overnight. The
15 combined organic extracts were dried over magnesium sulfate, filtered, and concentrated
under reduced pressure. The resulting brown solid (2.03 g) was dissolved in
dichloromethane (45 mL), purified by automated flash chromatography (40+M silica
cartridge, eluting with 3% to 10% methanol in ethyl acetate), and then triturated with
acetonitrile. The resulting solid was isolated by filtration, washed with acetonitrile, and
20 dried in a vacuum oven to provide 485 mg of 1 -[4-amino-7-(3,4-difluorophenyl)-2-
(ethoxymethyl)-l^-imidazo[4,5-c][l,5]naphthyridin-l-yl]-2-methylpropan-2-ol as an off-
white solid, mp 193-195 °C.
Anal, calcd for C 2 2H23F 2 N 5 02: C, 61.82; H, 5.42; N, 16.38. Found: C, 61.95; H, 5.46; N,
16.34.
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Example 60
l-[4-Amino-7-(3,4-dichlorophenyl)-2-(ethoxymethyl)-li^-imidazo[4,5-
c] [ 1 ,5]naphthyridin- 1 ~yl]-2-methylpropan-2-ol
5 A suspension of 1 -[4-amino-7-bromo-2-(ethoxymethyl)- li/-imidazo[4,5-
c][l,5]naphthyridin-l-yl]-2-methylpropan-2-ol (1.4 g, 3.55 mmol), 3,4-
difluorophenylboronic acid (1.36 g, 7.10 mmol), potassium carbonate (1.62 g, 1 1.7 mmol),
DME (13 mL), and water (7 mL) was stirred under nitrogen.
Dichlorobis(triphenylphosphine)palladium(II) (0.025 g, 0.036 mmol) was added, and the
1 0 suspension was heated at reflux for five hours and allowed to cool to room temperature.
The DME was removed under reduced pressure, and the resulting mixture was diluted
with water (20 mL) and extracted with dichloromethane (3 x 50 mL). An emulson
formed; the second extraction was allowed to stand overnight. The combined organic
extracts were dried over magnesium sulfate, filtered, and concentrated under reduced
1 5 pressure. The resulting brown solid (2.2 g) was dissolved in dichloromethane (1 5 mL),
purified as described in Example 59 to provide 264 mg of l-[4-amino-7-(3,4-
dichlorophenyl)-2-(ethoxymethyl)- 1 #-imidazo[4,5-c] [ 1 ,5]naphthyridin-l -yl]-2-
m.ethylpropan-2-ol as an off-white solid, mp 144-147 °C.
Anal, calcd for C^IfeCkNsOz: C, 57.40; H, 5.04; N, 15.21. Found: C, 57.11; H, 5.07; N,
20 14.99.
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Example 61
l-{4-Amino-2<ethoxymethyl)-7-[^^
c] [ 1 ,5]naphthyridin- 1 -yl} -2-methylpropan-2-ol
5 Under a nitrogen atmosphere, a suspension of 1 -[4-amino-7-bromo-2-
(ethoxymethyl)-li/-imidazo[4,5-c][l^ C 1 - 5 §> 3 - 8
mmol), 3-(morpholine-4-carbonyl)phenylboronic acid (1.07 g, 4.57 mmol), potassium
carbonate (1.74 g, 12.6 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.027 g,
0.038 mmol), DME (13 mL), and water (7 mL) was stirred in a pressure vessel. The
1 0 vessel was sealed, and the suspension was heated at 1 1 0 °C for 22 hours and allowed to
cool to room temperature. The DME was removed under reduced pressure, and the
resulting mixture was extracted with dichloromethane (3 x 25 mL) and ethyl acetate (25
mL). The combined organic extracts were dried over magnesium sulfate, filtered, and
concentrated under reduced pressure. The resulting tan solid (2.1 1 g) was dissolved in
1 5 dichloromethane ( 1 5 mL), purified by automated flash chromatography (40+M silica
cartridge, eluting with 5% to 20% methanol in ethyl acetate). The resulting foamy solid
was concentrated twice from methyl acetate, and the resulting solid was triturated with
acetonitrile, isolated by filtration, washed with acetonitrile, and dried in a vacuum oven to
provide 601 mg of l-{4-amino-2-(ethoxymethyl)-7-[3-(morpholin-4-ylcarbonyl)phenyl]-
20 liy-imidazo[4,5-c][l,5]naphthyridin-l-yl}-2-methylpropan-2-ol as a white solid, mp 149-
152 °C.
Anal, calcd for C27H32N6O4: C, 64.27; H, 6.39; N, 16.66. Found: C, 64.13; H, 6.62; N,
16.68.
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Example 62
l-[4-Amino-2-(ethoxyrnethyl)-7-(6-fluoropyridin-3-yl)-liY-imidazo[4,5-
c] [ 1 ,5]naprithyridin- 1 -yl] -2-methylpropan-2-ol
5 A suspension of 1 -[4-amino-7-bromo-2-(ethoxymethyl)- l/f-imidazo[4,5-
c][l,5]naphthyridin-l-yl]-2-meth.ylpropan-2-ol (1.4 g, 3.55 mmol), 6-fluoropyridine-3-
boronic acid (0.597 g, 4.26 mmol), potassium carbonate (1.62 g, 11.7 mmol),
dichlorobis(triphenylphosphine)palladium(n) (0.025 g, 0.036 mmol), DME (13 mL), and
water (7 mL) was stirred under a nitrogen atmosphere and then heated at 1 10 °C for 17.5
10 hours and allowed to cool to room temperature. The volatiles were removed under
reduced pressure, and the residue was partitioned between water (25 mL) and
dichloromethane (25 mL). A solid was present in the organic layer, and methanol was
added to dissolve the solid. The aqueous layer was extracted with dichloromethane (3 x
20 mL). Silica gel was added to the combined organic fractions, and the mixture was
1 5 concentrated under reduced pressure. The residue was purified by automated flash
chromatography (40+M silica cartridge, eluting with 5% to 15% methanol in ethyl acetate)
followed by recrystallization from acetonitrile. The crystals were isolated by filtration,
washed with acetonitrile, and dried in a vacuum oven to provide 530 mg of l-[4-amino-2-
(ethoxymethyl)-7-(6-fluoropyridin-3-yl)- lif-imidazo [4,5-c] [ 1 ,5]naphthyridin- 1 -yl]-2-
20 methylpropan-2-ol as white crystals, mp 218-220 °C.
Anal, calcd for C21H23FN6O2: C, 61.45; H, 5.65; N, 20.47. Found: C, 61.35; H, 5.55; N,
20.72.
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Example 63
A^-{3-[4-Amino-2Kethoxymethyl)-l-(2-hy(koxy-2-methylpropyl)-l^-imidazo[4,5-
c][l,5]naphthyridin-l-yl]phenyl}methanesulfonamide
5 A suspension of l-[4-amino-7-bromo-2-(ethoxymethyl)-17/-imidazo[4,5-
c][l,5]naphthyridin-l-yl]-2-methylpropan-2-ol (1.4 g, 3.55 mmol), (3-
methylsulfonylaminophenyl)boronic acid (0.916 g, 4.26 mmol), potassium carbonate (1.62
g, 11.7 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.025 g, 0.036 mmol), DME
(13 mL), and water (7 mL) was stirred under a nitrogen atmosphere and then heated at 1 10
10 °C for 1 8 .5 hours and allowed to cool to room temperature. An analysis by LC/MS
indicated the reaction was incomplete, and additional (3-
methylsulfonylaminophenyl)boronic acid (1.0 g) and
dichlorobis(triphenylphosphine)palladium(II) (0. 15 g) were added. The reaction was
heated at 1 10 °C for six hours and allowed to cool to room temperature. The volatiles
1 5 were removed under reduced pressure. The entire reaction mixture was diluted with
methanol, and silica gel was added. The mixture was concentrated under reduced
pressure. The residue was purified by chromatography according to the method described
in Example 62 followed by crystallization from methyl acetate (20 mL). The crystals were
isolated by filtration, washed with acetonitrile, and dried in a vacuum oven to provide 679
20 mg ofN- {3-[4-amino-2-(ethoxymethyl)-l-(2-hydroxy-2-methylpropyl)-lF-imidazo[4,5-
c][l,5]naphthyridin-l-yl]phenyl}methanesurfonamide as yellow crystals, mp 206-208 °C.
Anal, calcd for C 2 3H 28 N 6 0 4 S: C, 57.01; H, 5.82; N, 17.34. Found: C, 56.96; H, 5.82; N,
16.99.
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Example 64
l-[4-Amino-2-(ethoxymethyl)-7-phenyl-l/f-imidazo[4,5-c][l,5]naphthyri
methylpropan-2-ol
A suspension of l-[4-amino-7-bromo-2-(ethoxymethyl)-li ! y-imidazo[4,5-
c][l,5]naphthyridin-l-yl]-2-methylpropan-2-ol (1.55 g, 3.93 mmol), phenylboronic acid
(0.575 g, 4.72 mmol), potassium carbonate (1.79 g, 13.0 mmol),
dichlorobis(triphenylphosphine)palladium(II) (0.028 g, 0.039 mmol), DME (13 mL), and
water (7 mL) was stirred under a nitrogen atmosphere and then heated at reflux for 61
hours and allowed to cool to room temperature. The volatiles were removed under
reduced pressure. The residue was diluted with methanol, and silica gel was added. The
mixture was concentrated under reduced pressure. The residue was purified by
chromatography according to the method described in Example 59. The resulting foamy
solid (1.55 g) was concentrated twice from acetonitrile and then triturated with acetonitrile
(25 mL) to provide a solid. The solid was isolated by filtration, washed with acetonitrile,
and dried in a vacuum oven at 65 °C to provide 887 mg of l-[4-amino-2-(ethoxymethyl)-
7-phenyl-li7-imidazo[4,5-c][l,5]naphthyridin-l-yl]-2-methylpropan-2-ol as an off-white
solid, mp 158-159 °C.
Anal, calcd for C^EbNsOs: C, 67.50; H, 6.44; N, 17.89. Found: C, 67.27; H, 6.66; N,
18.08.
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Example 65
1 - {4-Amino-2-(ethoxymethyl)-7-[3-(pyrrolidin-l -ylcarbonyl)phenyl]-l#-imidazo[4,5-
c] [ 1 ,5]naphthyridin- 1 -yl} -2-methylpropan-2-ol
5 A suspension of l-[4-amino-7-bromo-2-(ethoxymethyl)-l//-imidazo[4,5-
c][l,5]naphthyridin-l-yl]-2-methylpropan-2-ol (1.2 g, 3.0 mmol), (3-
pyrrolidinylcarbonylphenyl)boronic acid (0.800 g, 3.65 mmol), potassium carbonate (1.4
g, 10.0 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.021 g, 0.030 mmol), DME
(13 mL), and water (7 mL) was stirred under a nitrogen atmosphere in a pressure vessel.
10 The vessel was then sealed and heated at 1 10 °C for 16.5 hours and allowed to cool to
room temperature. The volatiles were removed under reduced pressure. The residue was
diluted with methanol, and silica gel was added. The mixture was concentrated under
reduced pressure. The residue was purified by automated flash chromatography (FLASH
40+M silica cartridge, eluting with 10% to 25% methanol in ethyl acetate). The resulting
1 5 material was concentrated twice from acetonitrile and then triturated with acetonitrile (1 00
mL) to provide a solid. The solid was isolated by filtration, washed with acetonitrile, and
dried in a vacuum oven at 65 °C to provide 403 mg of 1 - {4-amino-2-(ethoxymethyl)-7-[3-
(pyrrolidin-l-ylcarbonyl)phenyl]-l^-imidazo[4,5-c][l,5]naphthyridin-l-yl}-2-
methylpropan-2-ol as a white solid, mp 185-187 °C.
20 Anal, calcd for C27H32N6O3: C, 66.37; H, 6.60; N, 17.20. Found: C, 66.26; H, 6.53; N,
17.26.
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Example 66
1 - {4- Amino-2-(ethoxymethyl)-7-[3-(hydroxymethyl)phenyl] -177-imidazo[4,5-
c][l,5]naphthyridin-l-yl]-2-methylpropan-2-ol
5 A suspension of 1 -[4-amino-7-bromo-2-(ethoxymethyl)- l#-imidazo[4,5-
c][l,5]naphthyridin-l-yl]-2-methylpropan-2-ol (1.2 g, 3.0 mmol), 3-
(hydroxymethyl)benzeneboronic acid (0.555 g, 3.65 mmol), potassium carbonate (1.4 g,
10.0 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.021 g, 0.030 mmol), DME
(13 mL), and water (7 mL) was stirred under a nitrogen atmosphere in a pressure vessel.
10 The vessel was then sealed and heated at 110 °C for 16.5 hours and allowed to cool to
room temperature. The volatiles were removed under reduced pressure. The residue was
diluted with methanol, and silica gel was added. The mixture was concentrated under
reduced pressure. The residue was purified by automated flash chromatography (FLASH
40+M silica cartridge, eluting with 5% to 20% methanol in ethyl acetate) followed by
1 5 trituration with acetonitrile. The resulting solid was isolated by filtration, washed with
acetonitrile, and dried in a vacuum oven at 65 °C to provide 449 mg of l-{4-amino-2-
(ethoxymethyl)-7-[3-(hydroxymethyl)phenyl]-l/^-imidazo[4,5-c][l,5]naphthyridin-l-yl]-
2-methylpropan-2-ol as a white solid, mp 186-187 °C.
Anal, calcd for C 2 3H 2 7N 5 0 3 : C, 65.54; H, 6.46; N, 16.62. Found: C, 65.47; H, 6.31; N,
20 16.67.
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Example 67
3 - [4- Amino-2-(ethoxymethyl)- 1 -(2-hydroxy-2-methylpropyl)- 1 //-imidazo [4,5-
c] [ 1 ,5]naphthyridin-7-yl]benzamide
A suspension of l-[4-amino-7-bromo-2-(ethoxymethyl)-li7-imidazo[4,5-
c][l,5]naphthyridin-l-yl]-2-methylpropan-2-ol (1.2 g, 3.0 mmol), (3-
aminocarbonylphenyl)boronic acid (0.603 g, 3.65 mmol), potassium carbonate (1.4 g, 10.0
mmol), dichlorobis(triphenylphosphine)palladium(II) (0.021 g, 0.030 mmol), DME (13
mL), and water (7 mL) was stirred under a nitrogen atmosphere in a pressure vessel. The
vessel was then sealed and heated at 1 10 °C for 64 hours and allowed to cool to room
temperature. A precipitate formed and was isolated by filtration, washed with water and
DME, and recrystallized from methanol (100 mL/900 mg). The crystals were isolated by
filtration, washed with methanol, and dried in a vacuum oven at 65 °C to provide 191 mg
of 3-[4-amino-2-(ethoxymethyl)-l-(2-hydroxy-2-methylpropyl)-li7-imidazo[4,5-
c][l,5]naphthyridin-7-yl]benzamide as an off-white solid, mp >250 °C.
Anal, calcd for C^E^NtA: C, 63.58; H, 6.03; N, 19.34. Found: C, 63.57; H, 6.16; N,
19.38.
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Example 68
1 - {4-Amino-2-(ethoxymethyl)-7-[5-(hydroxymethyl)pyridin-3 -yl] - l#-imidazo [4,5-
c] [ 1 ,5]naphthyridin-l -yl} -2-methylpropan-2-ol
5 Part A
A suspension of l-[4-amino-7-bromo-2-(ethoxymethyl)-l//-imidazo[4,5-
c][l,5]naphthyridin-l-yl]-2-methylpropan-2-ol (1.5 g, 3.80 mmol), 5-{tert-
butyldimethylsilanyloxymethyl)pyridine-3-boronic acid (1.22 g, 4.57 mmol), potassium
carbonate (1.74 g, 12.6 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.027 g,
10 0.038 mmol), DME (13 mL), and water (7 mL) was stirred under a nitrogen atmosphere
and then heated at 1 10 °C in a pressure vessel for 6 hours and allowed to cool to room
temperature. An analysis by LC/MS indicated the reaction was incomplete, and additional
dichlorobis(triphenylphosphine)palladium(II) (0.035 g) was added. The reaction was
heated at 1 10 °C for 16 hours and allowed to cool to room temperature. The DME was
1 5 removed under reduced pressure, and the resulting mixture was extracted with
dichloromethane (3 x 25 mL). The combined organic extracts were dried over magnesium
sulfate, filtered, and concentrated under reduced pressure. The resulting brown solid was
dissolved in dichloromethane (15 mL) purified by chromatography according to the
method described in Example 62 to provide 1.37 g of l-{4-amino-7-[5-(tert-
20 butyldimethylsilanyloxymethyl)pyridm-3-yl]-2-(ethoxymethyl)-li/-imidazo[4,5-
c][l,5]naphthyridin-l-yl]-2-methylpropan-2-ol as a yellow solid.
PartB
A solution of l-{4-amino-7-[5-(ter?-butyldimethylsilanyloxymethyl)pyridin-3-yl]-
2-(ethoxymethyl)-li/-imidazo[4,5-c][l,5]naphthyridin-l-yl]-2-methylpropan-2-ol (1 .37 g,
25 2.55 mmol) in acetic acid (10 mL), terrahydrofuran (10 mL), and water (10 mL) was
stirred at 60 °C for 18.5 hours and allowed to cool to room temperature. The solvent was
removed under reduced pressure, and the residue was diluted with saturated aqueous
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sodium bicarbonate (30 mL). Dichloromethane was added, but an oil was present that
remained insoluble in both phases. Both phases were decanted away from the oil, which
was dissolved in methanol. The aqueous phase was then separated and extracted with
dichloromethane (30 mL) and ethyl acetate (2 x 30 mL). Silica gel was added to the
5 combined dichloromethane, ethyl acetate, and methanol fractions, and the solvent was
removed under reduced pressure. The residue was purified by automated flash
chromatography (FLASH 40+M silica cartridge, eluting with 5% to 20% methanol in
dichloromethane). The resulting material was concentrated from acetonitrile to form a
solid, which was triturated with acetonitrile (30 mL), isolated by filtration, washed with
1 0 acetonitrile, and dried overnight in a vacuum oven to provide 530 mg of 1 - {4-amino-2-
(ethoxymethyl)-7-[5-(hydroxymethyl)pyridin-3-yl]-li/-imidazo[4,5-c][l,5]naphthyridin-
l-yl}-2-methylpropan-2-ol as a light yellow solid, mp 212-214 °C.
Anal, calcd for CzaHaeNgOa: C, 62.54; H, 6.20; N, 19.89. Found: C, 62.39; H, 6.09; N,
19.91.
15
Example 69
l-[4-Amino-7-(3,4-difluorophenyl)-2-(hydroxymethyl)-li3T-imidazo[4,5-
c] [ 1 ,5]naphthyridin-l -yl]-2-methylpropan-2-ol
20 A suspension of l-[4-amino-7-(3,4-difluorophenyl)-2-(ethoxymethyl)-l J f/-
imidazo[4,5-c][l,5]naphthyridin-l-yl]-2-methylpropan-2-ol (0.790 g, 1.85 mmol),
obtained from the filtrate from the trituration in Example 59, in dichloromethane (20 mL)
was cooled to 0 °C. Boron tribromide (5.54 mL of a 1 M solution in dichloromethane)
was added dropwise, and the reaction was stirred at room temperature for 22.5 hours. An
25 analysis by LC/MS indicated the reaction was incomplete, and additional boron tribromide
(2.7 mL) was added. The reaction was stirred for three hours at room temperature, and
then methanol (25 mL) was carefully added. The resulting solution was stirred at room
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temperature for one hour and concentrated under reduced pressure. A solution of
ammonia in methanol (30 mL of 2 M) was added, and the mixture was stirred for 30
minutes and then diluted with methanol (50 mL) and dichloromethane (50 mL). Silica gel
was added, and the mixture was concentrated under reduced pressure. The residue was
purified by chromatography according to the method described in Example 62. The
resulting solid was triturated with acetonitrile, isolated by filtration, washed with
acetonitrile, and dried in a vacuum oven to provide 269 mg of l-[4-amino-7-(3,4-
difluorophenyl)-2-(>yd^oxymethyl)-li/-imidazo[4,5-c][l,5]naphthyridin-l-yl]-2-
methylpropan-2-ol as a light yellow solid, mp 256-258 °C.
Anal, calcd for C 2 oHi9F 2 N 5 02: C, 60.15; H, 4.80; N, 17.53. Found: C, 60.15; H, 4.74; N,
17.80.
Example 70
l-[4-Amino-7-(3,4-dichlorophenyl)-2-(hydroxymethyl)-l/7-imidazo[4,5-
c] [ 1 ,5]naphthyridin- 1 -yl] -2-methylpropan-2-ol
A solution of l-[4-amino-7-(3,4-dichlorophenyl)-2-(ethoxymethyl)-li/-
imidazo[4,5-c][l,5]naphthyridin-l-yl]-2-methylpropan-2-ol (0.850 g, 1.85 mmol),
obtained from the filtrate from the trituration in Example 60, in dichloromethane (20 mL)
was cooled to 0 °C. Boron tribromide (5.5 mL of a 1 M solution in dichloromethane) was
added dropwise, and the reaction was stirred at room temperature for 24 hours. An
analysis by LC/MS indicated the reaction was incomplete, and additional boron tribromide
(5.5 mL) was added. The reaction was stirred for three hours at room temperature, and the
work-up and purification procedures described in Example 69 were followed to provide
233 mg of l-[4-amino-7-(3,4-dichlorophenyl)-2-(hydroxymethyl)-l//-imidazo[4,5-
c] [ 1 ,5]naphthyridin- 1 -yl]-2-methylpropan-2-ol, mp 254-256 °C.
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Anal, calcd for C20H19CI2N5O2: C, 55.57; H, 4.43; N, 16.20. Found: C, 55.50; H, 4.58; N,
16.01.
Example 71
5 1 - {4~Amino-2-(hydroxymethyl)-7-[3-(morpto
c] [ 1 ,5]naphthyridin- 1 -yl} -2-methylpropan-2-ol
A solution of l-{4-amino-2-(ethoxymethyl)-7-[3-(morpholin-4-
ylc arbonyl)phenyl]- l#-imidazo[4,5-c] [ 1 ,5]naphthyridin- 1 -yl} -2-methylpropan-2-ol (1.10
10 g, 2.18 mmol), obtained from the filtrate from the trituration in Example 61, in
dichloromethane (20 mL) was cooled to -78 °C. Boron tribromide (10.9 mL of a 1 M
solution in dichloromethane) was added dropwise, and the reaction was allowed to warm
to room temperature and stirred for 5.5 hours. Methanol (20 mL) was carefully added, and
the resulting solution was stirred at room temperature for one hour and concentrated under
1 5 reduced pressure. A solution of ammonia in methanol (50 mL of 1 M) was added, and the
mixture was stirred for one hour. Silica gel was added, and the mixture was concentrated
under reduced pressure. The resulting mixture was purified according to the methods
described in Example 61 with the modification that chromatographed material was
concentrated from acetonitrile instead of methyl acetate. l-{4-Amino-2-(hydroxymethyl)-
20 7-[3-(morpholin-4-ylcarbonyl)phenyl]-li7-imidazo[4,5-c] [1 ,5]naphthyridin-l-yl} -2-
methylpropan-2-ol (307 mg) was obtained as a light yellow solid, mp 153-155 °C.
Anal, calcd for C, 63.01; H, 5.92; N, 17.64. Found: C, 62.92; H, 5.67; N,
17.51.
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Example 72
7V'-{344-Amino-2-(hydroxymemyl)-l-(2-hydroxy-2-methylpropyl)-liy-
c] [ 1 ,5]naphthyridin- 1 -yl]phenyl}methanesulfonamide
A suspension of 7Y-{3-[4-ammo-2-(ethoxymethyl)-l-(2-hydroxy-2-methylpropyl)-
l/f-imidazo[4,5-c][l,5]naphthyridin-l-yl]phenyl}methanesulfonamide (1.17 g, 2.41
mmol), obtained from the filtrate from the recrystallization in Example 63, in
dichloromethane (20 mL) was cooled to 0 °C. Boron tribromide (12.1 mL of a 1 M
solution in dichloromethane) was added dropwise, and the reaction was stirred at room
temperature for 22 hours. Methanol (40 mL) was carefully added, and the resulting
solution was stirred at room temperature for one hour and concentrated under reduced
pressure. A solution of ammonia in methanol (100 mL of 1 M) was added, and the
mixture was stirred at room temperature and then concentrated under reduced pressure.
The residue was triturated with methanol (50 mL), and the resulting solid was isolated by
filtration and washed with methanol and acetonitrile. The solid (710 mg) was then
recrystallized from acetonitrile. The crystals were isolated by filtration, washed with
acetonitrile, and dried in a vacuum oven to provide 493 mg of 7Y-{3-[4-amino-2-
(hydroxymethyl)- 1 -(2-hydroxy-2-methylpropyl)- l#-imidazo[4,5-c] [ 1 ,5]naphthyridin- 1 -
yl]phenyl}methanesulfonamide as a yellow solid, mp > 250 °C.
Anal, calcd for C21H24N6O4S: C, 55.25; H, 5.30; N, 18.41. Found: C, 54.99; H, 5.06; N,
18.26.
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Example 73
1 ^4-Amino-2-(hydroxymethyl)-7-phenyl-li?-imidazo[4,5-c] [ 1 ,5]naphthyridin- 1 -yl]-2-
methylpropan-2-ol
5 A solution of l-[4-amino-2-(ethoxymethyl)-7-phenyl-l J f/-imidazo[4,5-
c][l,5]naphthyridin-l-yl]-2-methylpropan-2-ol (1.0 g, 2.55 mmol), obtained from the
filtrate from the trituration in Example 64, in dichloromethane (25 mL) was cooled to 0
°C. Boron tribromide (12.8 mL of a 1 M solution in dichloromethane) was added
dropwise, and the resulting suspension was stirred at room temperature for 14.5 hours.
10 Methanol (50 mL) was carefully added, and the resulting solution was stirred at room
temperature for one hour and concentrated under reduced pressure. A solution of
ammonia in methanol (50 mL of 1 M) was added, and the suspension was stirred at room
temperature for three hours. A solid was isolated by filtration, washed with methanol and
acetonitrile, and dried in a vacuum oven at 65 °C to provide 403 mg of l-[4-amino-2-
15 (hydroxymethyl)-7-phenyl4/^-inaidazo[4,5-c][l,5]naphthyridin-l-yl]-2-methylpropan-2-
ol as a white solid, mp 244-245 °C.
Anal, calcd for C 2 oH2iN 5 02: C, 66.10; H, 5.82; N, 19.27. Found: C, 65.90; H, 5.77; N,
19.34.
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Example 74
l-{4-Amino-2-(hydroxymethyl)-7-[3-(hydro
c] [ 1 ,5]naphthyridin- 1 -yl]-2-methylpropan-2-ol
5 A suspension of 1 - {4-amino-2-(ethoxymethyl)-7-[3-(hydroxymethyl)phenyl]- \H-
imidazo[4,5-c][l,5]naphthyridin-l-yl]-2-methylpropan-2-ol (0.800 g, 1.90 mmol) obtained
from the filtrate from the trituration in Example 66, in dichloromethane (20 mL) was
cooled to 0 °C. Boron tribromide (9.5 mL of a 1 M solution in dichloromethane) was
added dropwise, and the resulting suspension was stirred at room temperature for 15
10 hours. Methanol was carefully added, and the resulting solution was stirred at room
temperature for one hour and concentrated under reduced pressure. The residue (1.33 g)
was dissolved in DMF (15 mL), and potassium acetate was added. The mixture was
heated at 50 °C for 18 hours and then concentrated under reduced pressure. The residue
was dissolved in methanol (20 mL) and water (lO mL), and lithium hydroxide
1 5 monohydrate (1 .5 g) was added. The reaction was stirred at room temperature for 64
hours and concentrated under reduced pressure. Methanol and silica gel were added, and
the mixture was concentrated under reduced pres sure. The residue was purified by ,
automated flash chromatography (FLASH 40+M cartridge, eluting with 7% to 20% 1 M
methanolic ammonia in dichloromethane) followed by recrystallization from acetonitrile
20 after a hot filtration. The crystals were washed with acetonitrile and dried in a vacuum
oven at 65 °C to provide 146 mg of l-{4-amino-2-(hydroxymethyl)-7-[3-
(hydroxymethyl)phenyl]- 1 iiT-imidazo [4,5-c] [ 1 , 5] naphthyridin- 1 -yl] -2-methylpropan-2-ol
as a yellow solid, mp 227-229 °C.
Anal, calcd for C 2 iH23N 5 O 3 -0.1H 2 O: C, 63.82; FX, 5.92; N, 17.72. Found: C, 63.62; H,
25 5.93; N, 17.79.
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Example 75
1 - {4-Amino-2-(hydroxymethyl)-7-[3-(pyrrolidin- 1 -ylcarbonyl)phenyl]- l//-imidazo[4,5-
c] [ 1 ,5]naphthyridin- 1 -yl} -2-methylpropan-2-ol
5 A solution of 1 - {4-amino-2-(ethoxymethyl)-7-[3-(pyrrolidin- 1 -ylcarbonyl)phenyl]-
l^midazo[4,5-c][l,5]naphthyridin-l-yl}-2-methylpropan-2-ol (1.0 g, 2.0 mmol),
obtained from the filtrate from the trituration in Example 65, in dichloromethane (20 mL)
was cooled to 0 °C. Boron tribromide (10.2 mL of a 1 M solution in dichloromethane)
was added dropwise, and the reaction was allowed to warm to room temperature and
10 stirred for 15 hours. Methanol (50 mL) was carefully added, and the resulting solution
was stirred at room temperature for one hour and concentrated under reduced pressure. A
solution of ammonia in methanol (50 mL of 1 M) was added, and the mixture was stirred
for one hour. Silica gel was added, and the mixture was concentrated under reduced
pressure. The resulting mixture was purified by automated flash chromatography (FLASH
15 40+M cartridge, eluting with 5% to 20% methanolic ammonia in dichloromethane),
triturated with acetonitrile, isolated by filtration, washed with acetonitrile, and dried in a
vacuum oven at 65 °C to provide 169 mg of l-{4-amino-2-(hydroxymethyl)-7-[3-
(pyrrolidin-1 -ylcarbonyl)phenyl]-li/-imidazo[4,5-c] [ 1 ,5]naphthyxidin- 1 -yl} -2-
methylpropan-2-ol as an off-white solid, mp 157 - 160 °C.
20 Anal, calcd for C 25 H28N 6 O3-0.5 H 2 0: C, 63.95; H, 6.23; N, 17.90. Found: C, 63.59; H,
5.87; N, 17.97.
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Example 76
l-{4-Amino-2-(hydroxymethyl)-7-[5-(hycfroxym
c][l,5]naphthyridin-l-yl}-2-methylpropan-2-ol
5 A suspension of 1 - {4-amino-2-(ethoxymethyl)-7-[5-(hydroxymethyl)pyridin-3-yl]-
l//-imidazo[4,5-c][l,5]naphthyridin-l-yl}-2-methylpropan-2-ol (627 mg, 1.48 mrrioi),
obtained from the filtrate from the trituration in Example 68, in dichloromethane (25 mL)
was cooled to -78 °C. Boron tribromide (15 mL of a 1 M solution in dichloromethane)
was added dropwise, and the reaction was allowed to warm to room temperature and
10 stirred for 3.5 hours. Methanol (50 mL) was carefully added, and the resulting solution
was stirred at room temperature for 30 minutes and concentrated under reduced pressure.
A solution of ammonia in methanol (50 mL of 1 M) was added, and the mixture was
stirred for 30 minutes. Silica gel was added, and the mixture was concentrated under
reduced pressure. The resulting mixture was purified by automated flash chromatography
1 5 (FLASH 40+M cartridge, eluting with 15% to 30% methanolic ammonia in
dichloromethane). All fractions containing product were combined and concentrated, and
the residue was dissolved in methanol (50 mL) and treated with 6 M hydrochloric acid.
The solution was heated at 50 °C for two hours, concentrated under reduced pressure, and
diluted with 2 N ammonia in methanol. Silica gel was added, and the mixture was
20 concentrated under reduced pressure. Chromatographic purification was carried out again
as described above with the modification that the elution gradient began with 5%
methanolic ammonia in dichloromethane. The resulting product was dissolved in
methanol (20 mL), divided in ten equal portions, and loaded onto ten Waters Oasis Sample
Extractions Cartridge MCX columns (500 mg) according to the following procedure.
25 Each column was washed with methanol (2 volumes) and 1 N ammonia in methanol (3
volumes), and the ammonia washes were combined and concentrated under reduced
pressure. The resulting solid (200 mg) was triturated with acetonitrile, isolated by
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filtration, washed with acetonitrile, and dried in a vacuum oven to provide 175 mg of 1-
{4-amino-2-(hydroxymethyl)-7-[5-(hy&oxym
c][l,5]naphthyridin-l-yl}-2-methylpropan-2-ol as a light yellow solid, mp 149-151 °C.
Anal, calcd for C20H22N6O3: C, 60.90; H, 5.62; N, 21.31. Found: C, 60.75; H, 5.69; N,
5 21.40.
Examples 77-127
A solution of l-[4-amino-7-bromo-2-(ethoxymethyl)-l//-imidazo[4,5-
c][l,5]naphthyridin-l-yl]-2-methylpropan-2-ol (42.0 mg, 0.11 mmol) in 7:3
10 volume:vomme (v:v) chloroform:methanol (2 mL) was added to a test tube, and the
solvent was removed by vacuum centrifugation. The boronic acid (0.12 mmol) indicated
in the table below and n-propanol (1.6 mL) were sequentially added. Palladium (II)
acetate (0.150 mL of a 4 mg/mL solution in toluene, 0.0027 mmol), 2 M aqueous sodium
carbonate solution (600 uL), deionized water (113 uL), and a solution of 0.15 mol%
15 triphenylphosphine in rc-propanol (53 uL, 0.0078 mmol) were sequentially added. The
test tube was purged with nitrogen, capped, and then heated at 80 °C overnight in a sand
bath.
The contents of each test tube were passed through a Waters Oasis Sample
Extractions Cartridge MCX (6 cc) according to the procedure described in Examples 4 -
20 58. The resulting basic solutions were concentrated by vacuum centrifugation. The
compounds were purified by reversed phase prep HPLC using a Waters FractionLynx
automated purification system. The prep HPLC fractions were analyzed using a Waters
LC/TOF-MS, and the appropriate fractions were centrifuge evaporated to provide the
trifluoroacetate salt of the desired compound. Reversed phase preparative liquid
25 chromatography was performed with non-linear gradient elution from 5-95% B where A is
0.05% trifluoroacetic acid/water and B is 0.05% trifluoroacetic acid/acetonitrile. Fractions
were collected by mass-selective triggering. The table below shows the reagent added to
each test tube, the structure of the resulting compound, and the observed accurate mass for
the isolated trifluoroacetate salt.
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Examples 77 - 127
NH 2 CH 3
II T \ ch 3
A^-N ^fcH 3
R OH
Example
Reagent
R
Measured
Mass
(M+H)
None
Br""
394.0867
77
Furan-3-boronic acid
382.1894
78
Pyridine-3-boronic acid
393.2059
79
Pyridine-4-boronic acid
393.2078
80
3-Methylphenylboronic acid
0"
CH
406.2238
81
4-Methylphenylboronic acid
H 3 C^CX
406.2264
82
o-Tolylboronic acid
OC,
406.2216
83
2-Hydroxyphenylboronic acid
oc
408.2068
84
3 -Hydroxyphenylboronic acid
Co
OH
408.2061
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85
4-Cyanophenylboronic acid
417.2075
86
4-Vinylphenylboronic acid
418.2259
87
3,5-Dimethylphenylboronic acid
CH 3
420.2406
88
4-Ethylphenylboronic acid
420.2379
89
2-Methoxyphenylboronic acid
oc
CH 3
422.2213
90
4-(Hydroxymethyl)phenylboronic
acid
&
OH
422.2196
91
4-Methoxyphenylboronic acid
CH 3
422.2149
92
3-Aminophenylboronic acid
monohydrate
gr
NH 2
407.2189
93
(4-Fluoro-2-hydroxy)phenylboronic
acid
426.1971
94
3-Chlorophenylboronic acid
426.1695
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95
2-Chlorophenylboronic acid
OC
426.1694
96
4-Chlorophenylboronic acid
426.1713
97
2,4-Difluorophenylboronic acid
428.1916
98
Benzo[Z?]furan-2-boronic acid
432.2041
99
3-Acetylphenylboronic acid
V
0 A CH 3
434.2236
100
4-Acetylphenylboronic acid
0
434.2192
101
3 ,4-Methylenedioxyphenylboronic
acid
&
436.1993
102
3-Carboxyphenylboronic acid
O^OH
436.2005
103
4-Carboxyphenylboronic acid
o
436.1992
104
2-Ethoxyphenylboronic acid
^CH 3
436.2338
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105
3-Ethoxyphenylboronic acid
(X
r°
CH 3
436.2353
106
4-(Methyltliio)phenylboronic acid
CH 3
438.1939
107
2-Ethoxy-5-methylphenylboronic
acid
€C
k CH 3
450.2491
108
2-Isopropoxyphenylboronic acid
H 3 C CH 3
450.2470
109
4-Isopropoxyphenylboronic acid
H 3 C^CH 3
450.2492
110
[ 3 - (Hy droxypropyl)phenyl]boronic
acid
cr
J
450.2535
111
3,4-Dimethoxyphenylboronic acid
CY
°CH 3
452.2313
112
3-(4-Boronophenyl)propionic acid
XX
o
464.2318
104
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113
4-(Methoxycarobonylamino)phenyl-
boronic acid
CH,
465.2205
114
4-
(Cyclopropylaminocarbonyl)phenyl~
boronic acid
475.2462
115
3-(N-
Isopropylaminocarbonyl)phenyl-
boronic acid
1
HN^O
H 3 C^CH 3
477.2596
116
3-(iV-Propylaminocarbonyl)phenyl-
boronic acid
HN^O
CH 3
477.2637
117
4-Borono-i3Z-phenylalanine
0
479.2398
118
3,4,5-Trimethoxyphenylboronic acid
9H 3
CH, o
3 ° CH 3
482.2416
119
4-(Ethylsulfonyl)phenylboronic acid
484.2023
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120
3-(2-Cyanoethylaminocarbonyl)-
phenylboronic acid
7
HN^O
{
N
488.2415
121
3-(Isobutylaminocarbonyl)phenyl-
boronic acid
HN O
H 3 C r ^
CH 3
491.2749
122
4-(Isobutylaminocarbonyl)phenyl-
boronic acid
H 3 C CH 3
491.2750
123
carbonyl)phenylboronic acid
or
O 0
503.2775
124
4-(Cyclopentylaminocarbonyl)-
phenylboronic acid
a"
503.2757
125
4-Benzyloxy-3-fluorophenylboronic
acid
516.2405
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126
3 - (iV-B enzylamino c arbonyl)phenyl-
boronic acid
7
HN 0
525.2625
127
1 -(Phenylsulfonyl)- l//-indol-3 -
ylboronic acid
571.2138
Examples 128-151
A solution of l-[4-amino-7-bromo-2-(ethoxymethyl)-li/-imidazo[4,5-
c][l,5]naphthyridin-l-yl]-2-meth.ylpropan-2-ol (53.0 mg, 0.135 mmol) in 7:3
5 volume:volume (v:v) chloroform :methanol (2 mL) was added to a test tube, and the
solvent was removed by vacuum centrifugation. The boronic acid (0.16 mmol) indicated
in the table below and n-propanol (1.6 mL) were sequentially added. Palladium (II)
acetate (0.198 mL of a 4 mg/niL solution in toluene, 0.0035 mmol), 2 M aqueous sodium
carbonate solution (813 uL), deionized water (113 uL), and a solution of 0.15 mol%
10 triphenylphosphine in n-propanol (70 uL, 0.0078 mmol) were sequentially added. The
test tube was purged with nitrogen, capped, and then heated at 80 °C overnight in a sand
bath. Each sample was purified using Waters Oasis Sample Extractions Cartridge MCX
according to the method described in Examples 4-58, and the resulting basic solution
was concentrated by vacuum ceritrifugation. The residue from each tube was dissolved in
15 dichloromethane (1 mL) with the aid of sonication. Each tube was placed in an ice bath
for five minutes to cool to 0 °C, and then boron tribromide (0.640 mL of a 1 M solution in
dichloromethane) was added. Trie solution was vortexed, stirred at 0 °C for 30 minutes,
and then stirred overnight at room temperature. Methanol (1 mL) and 6 N hydrochloric
acid (0.500 mL) were added to each tube. The contents were vortexed, and the volatiles
20 were removed by vacuum centrifugation. The compounds were purified by reversed phase
prep HPLC according to the method described in Examples 77 - 127. The table below
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shows the reagent added to each test tube, the structure of the resulting compound, and the
observed accurate mass for the isolated trifluoroacetate salt.
Examples 128-151
NH 2
\\ T \ ch 3
K OH
Example
Reagent
R
Measured
Mass
(M+H)
Br
366.0562
128
3-Methylphenylboronic acid
CH 3
378.1936
129
4-Methylphenylboronic acid
378.1937
130
o-Tolylboronic acid
oc.
378.1938
131
2-Hydroxyphenylboronic acid
oc.
380.1721
132
3-Hydroxyphenylboronic acid
cr
OH
380.1718
133
3,5-Dimethylphenylboronic acid
HaC pr
CH 3
392.2099
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134
4-Ethylphenylboronic acid
CH 3
392.2090
135
(2-Hydroxymethylphenyl)boronic
acid dehydrate
cx,
OH
394.1907
136
3-Chlorophenylboronic acid
398.1390
137
4-Chlorophenylboronic acid
JX
398.1394
138
4-Acetylphenylboronic acid
0
406.1883
139
3,4-Dichlorophenylboronic acid
Xf
CI
432.1010
140
3-(N,N-
Dimethylaminocarbonyl)phenyl-
boronic acid
CH 3
435.2148
141
3-(N-
Isopropylaminocarbonyl)phenyl-
boronic acid
T
H,C CH S
449.2317
142
3-(A^-Propylaminocarbonyl)phenyl-
boronic acid
9"
CH 3
449.2323
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143
3 -(Methylsulfonylamino)phenyl-
boronic acid
(X
V
0,„-NH
457.1663
144
3-(2-Cyanoethylaminocarbonyl)-
phenylboronic acid
HN^O
{
N
460.2130
145
4-( Pyrrolidine- 1-
carbonyl)phenylboronic acid
(!)
461.2330
146
3-
(Butylaminocarbonyl)phenylboronic
acid
9"
HN^O
J
463.2459
147
3-(Isobutylaminocarbonyl)phenyl-
boronic acid
HN^O
H 3 C r J
CH 3
463.2463
148
4-(Isobutylaminocarbonyl)phenyl-
boronic acid
H 3 C A CH 3
463.246L
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149
3-(Piperidine-l-
carbonyl)phenylboronic acid
cx
I
0 0
475.2453
150
phenylboronic acid
475.2463
151
(4-Aminomethylphenyl)boronic
acid, pinacol ester, hydrochloride
NH 2
393.2034
Preparation of 1 -(4-Aniino-7-bromo-2-ethyl- l#-imidazo[4,5-c] [ 1 ,5]naphthyridin-l -yl)-2-
methylpropan-2-ol
NH,
Part A
Pyridine hydrochloride (0.095 g, 0.82 mmol) and triethyl orthopropionate (6.36 g,
36.1 mmol) were sequentially added to a solution of l-[(3-amino-7-
bromo[l,5]naphthyridin-4-yl)amino]-2-methylpropan-2-ol (10.2 g, 32.8 mmol) in toluene
(200 mL), and the resulting mixture was heated at reflux for three hours. Most of the
solvent was removed under reduced pressure, and a solid was present. The solid was
isolated by filtration and dried to provide 8.59 g of l-(7-bromo-2-ethyl-li/-imidazo[4,5-
c][l,5]naphthyridin-l-yl)-2-methylpropan-2-ol as a light yellow solid. A small portion of
the solid was recrystallized from acetonitrile to provide an off-white solid, mp 207-208 °C.
Anal, calcd for Ci 5 Hi 7 BrN 4 0: C, 51.59; H, 4.91; N, 16.04. Found: C, 51.27; H, 4.62; N,
15.78.
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PartB
mCPBA (1 1.2 g of 75% purity, 48.7 mmol) was added to a stirred solution of l-(7-
bromo-2-emyl-l#-imidazo[4,5-c][l,5]naphm^ (8.5 g, 24
mmol) in dichloromethane (150 mL), and the reaction was stirred at room temperature
overnight. The reaction mixture was diluted with dichloromethane (100 mL), washed
sequentially with 4% aqueous sodium carbonate (2 x 150 mL) and brine (1 x 150 mL), and
concentrated under reduced pressure. The residue was dissolved in dichloromethane (150
mL), and concentrated ammonium hydroxide (80 mL) was added. The mixture was stirred
vigorously and cooled to 4 °C, and then ji?-toluenesulfonyl chloride (5.80 g, 30.4 mmol)
was added in portions. The reaction mixture was stirred at room temperature for 16 hours
and diluted with dichloromethane (200 mL). A solid was present and was isolated by
filtration, washed well with water and acetonitrile, and dried to provide 2.94 of l-(4-
amino-7-bromo-2-ethyl- l#-imidazo[4,5-c] [ 1 ,5]naphthyridin-l -yl)-2-methylpropan-2-ol.
The organic layer was separated and washed with 4 N aqueous sodium carbonate (2 x 150
mL). The combined washings were extracted with dichloromethane (100 mL), and the
combined organic fractions were washed with brine, dried over sodium sulfate, filtered,
and concentrated under reduced pressure. The residue was triturated with acetonitrile to
provide an additional 1.36 g of l-(4-amino-7-bromo-2-ethyl-l#-imidazo[4,5-
c][l,5]naphthyridin-l-yl)-2-methylpropan-2-ol as an off-white solid, mp 235-236 °C.
Anal, calcd for Ci 5 H 18 BrN 5 0: C, 49.46; H, 4.98; N, 19.23. Found: C, 49.19; H, 4.84; N,
19.21.
l-[4-Amino-2-ethyl-7-(6-fluoropyridm^^
F N
2-Fluoropyridine-5-boronic acid (0.468 g, 3.32 mmol) was added to l-(4-amino-7-
bromo-2-ethyl-liJ-imidazo[4,5-c][l,5]naph1hyridin-l-yl)-2-methylpropan-2-ol (1.1 g, 3.0
Example 152
methylpropan-2-ol
NH 2
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mmol) and 1-propanol (10 mL). The mixture was degassed and backfilled with nitrogen.
Triphenylphosphine (23.8 mg, 0.0900 mmol), aqueous sodium carbonate (4.53 mL of 2
M), and water (2 mL) were added followed by palladium (II) acetate (6.8 mg, 0.030
mmol). The yellow suspension was heated at reflux for two hours. Water (20 mL) was
added, and the 1-propanol was removed under reduced pressure. The remaining mixture
was extracted with chloroform (2 x 100 mL). The combined extracts were washed with
brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The
crude product was triturated with acetonitrile and isolated by nitration to provide 0.84 g of
l-[4-amino-2-ethyl-7-(6-fluoropyridin-3-ylH
methylpropan-2-ol as a white powder, mp 250-251 °C.
Anal, calcd for C 2 oH 2 iFN 6 0: C, 63.15; H, 5.56; N, 22.09. Found: C, 63.03; H, 5.83; N,
22.13.
Example 153
1 -[4-Amino-2-ethyl-7-(quinolin-3-yl)- l#-imidazo [4,5-c] [ 1 ,5]naphthyridin- 1 -yl)-2-
methylpropan-2-ol
The method described in Example 152 was used to treat l-(4-amino-7-bromo-2-
ethyl-lif-imidazo^^-cJtLSJnaphthyridin-l-yO^-methylpropan^-ol (1.0 g, 2.7 mmol)
and 3-quinolineboronic acid (0.52 g, 3.0 mmol) in 1-propanol (10 mL) with
triphenylphosphine (21.6 mg, 0.0820 mmol), aqueous sodium carbonate (4.1 mL of 2 M),
water (2 mL), and palladium (II) acetate (6.2 mg, 0.027 mmol) with the following
modifications. The reaction mixture was heated at reflux for four hours. The crude
product was purified by recrystallization from ethyl acetate to provide 0.58 g of l-[4-
amino-2-ethyl-7-(qumolin-3-yl)-m-imidazo[4,5-c][l,5]naphthyridin-l-yl)-2-
methylpropan-2-ol as beige needles, mp > 270 °C.
Anal. Calcd for C 24 H 24 N 6 (>0.3HC1: C, 68.08; H, 5.78; N, 19.85. Found: C, 67.74; H,
5.63; N, 19.79.
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Examples 154-194
A solution of l-(4-ammo-7-bromo-2-emyl-l/f-imidazo[4,5-c][l,5]naphthyridin-l-
yl)-2-methylpropan-2-ol (36.4 mg, 0.10 mmol) in 7:3 volume:volume (v:v)
chloroform:methanol (2 mL) was added to a test tube, and the solvent was removed by
vacuum centrifugation. The boronic acid (0.1 1 mmol) indicated in the table below and n-
propanol (1 .6 mL) were sequentially added. The test tube was purged with nitrogen.
Palladium (II) acetate (0.150 mL of a 4 mg/mL solution in toluene, 0.0027 mmol), 2 M
aqueous sodium carbonate solution (600 |jL), deionized water (113 uL), and a solution of
0.15 mol% triphenylphosphine in «-propanol (53 uL, 0.0078 mmol) were sequentially
added. The test tube was purged with nitrogen, capped, and then heated at 80 °C overnight
in a sand bath. Methanol (1 mL) was added to each reaction, which was heated at 80 °C
for six hours.
The contents of each test tube were passed through a Waters Oasis Sample
Extractions Cartridge MCX (6 cc) according to the procedure described in Examples 4 -
58. The resulting basic solutions were concentrated by vacuum centrifugation. The
compounds were purified by reversed phase prep HPLC according to the method
described in Examples 77 - 127. The table below shows the reagent added to each test
tube, the structure of the resulting compound, and the observed accurate mass for the
isolated trifluoroacetate salt.
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Examples 154-194
NH
n-^t n ^ ch 3
\ \ ch_
R A^N ^fcH 3
K OH 3
Example
Reagent
R
Measured
Mass
(M+H)
None
Br^
364.0771
154
Phenylboronic acid
a
362.1984
155
Pyridine-3-boronic acid
a
363.1940
156
3-Methylphenylboronic acid
v tx
376.2139
157
4-Methylphenylboronic acid
H 3 C^^
376.2125
158
o-Tolylboronic acid
CH,
(X
376.2099
159
2-Hydroxyphenylboronic acid
OH
(X
378.1943
160
3-Hydroxyphenylboronic acid
"XX
378.1950
161
3-Cyanophenylboronic acid
387.1916
115
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162
4-Cyanophenylboronic acid
N
387.1917
163
2-Methoxyphenylboronic acid
H 3 C 0
cy
392.2068
164
4-
(Hydroxymethyl)phenylboronic
acid
ho^^O^
392.2070
165
4-Methoxyphenylboronic acid
392.2078
166
(4-Fluoro-2-
hydroxy)phenylboronic acid
OH
,&
396.1834
167
3-Chlorophenylboronic acid
"XT
396.1577
168
2-Chlorophenylboronic acid
CI
(X
396.1611
169
2,4-Difluorophenylboronic acid
F
398.1794
170
(3-Aminocarbonylphenyl)-
boronic acid
NH 2
oK cr
405.2054
171
[3-(Hydroxypropyl)phenyl]-
boronic acid
420.2407
172
2,4-Dimethoxyphenylboronic
acid
H,C 0
H 3 c. 0 iy
422.2228
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173
2,6-Dimethoxyphenylboronic
acid
H 3 C 0
1
6;
CH 3
422.2192
174
3 ,4-Dimethoxyphenylboronic
acid
CH 3
422.2192
175
3 ,4-Dichlorophenylboronic
xx
CI
430.1209
176
4-(4,4,5,5-Tetramethyl-l,3,2-
dioxaborolan-2-yl- 1 //-pyrazole
N
352.1907
177
4-(Methoxycarobonylamino)-
phenylboronic acid
0 ffV"
H 3 C 0 A N A ^
H
435.2133
178
4-(Methanesulfonyl)phenyl-
boronic acid
o«jCr
440.1761
179
4-
(Cyclopropylaminocarbonyl)-
phenylboronic acid
h
X
445.2351
180
3-(A^-Isopropylaminocarbonyl)-
phenylboronic acid
CH 3 0
447.2488
181
3-(7V-Propylaminocarbonyl)-
phenylboronic acid
0
H u
447.2490
182
3,4,5-
Trimethoxyphenylboronic acid
CH 3
°CH 3
452.2300
117
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183
4-(Ethylsulfonyl)phenylboronic
acid
o,XX
HP
454.1888
184
3-(Methylsulfonylamino)-
phenylboronic acid
455.1872
185
4-(Methylsulfonylamino)-
phenylboronic acid
H
455.1880
186
3 -(Pyrrolidine- 1-
carbonyl)phenylboronic acid
459.2503
187
4-(Pyrrolidirie-l-
carbonyl)phenylboronic acid
o
459.2505
188
3 -(Butylaminocarbonyl)-
phenylboronic acid
0
KJ
461.2662
189
3-(Isobutylaminocarbonyl)-
phenylboronic acid
0
ch 3 h
461.2663
190
4-(Isobutylaminoc arbonyl)-
phenylboronic acid
0
461.2668
191
3-(Piperidine-l-
carbonyl)phenylboronic acid
o
473.2675
192
4-(Cyclopentylaminocarbonyl)-
phenylboronic acid
473.2658
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193
3-(Morpholine-4-
carbonyl)phenylboronic acid
475.2444
194
3-(7V-Benzylaminocarbonyl)-
phenylboronic acid
o
U H U
495.2519
Preparation of l-[4-Amino-7-bromo-2-(2-methoxyethyl)-li/-imidazo[4,5-
c][l,5]naphthyridin-l-yl]-2-methylpropan-2-ol
5 Part A
Triethylamine (35.95 mL, 257.9 mmol) was added to a suspension of 7-bromo-4-
chloro-3-nitro[l,5]naphthyridine (49.6 g, 172 mrnol) in dichloromethane (500 mL). 1-
Amino-2-methylpropan-2-ol (16.86 g, 189 mmol) was added dropwise. The reaction
mixture was stirred at ambient temperature for 1 6 hours and then concentrated under
10 reduced pressure. The residue was triturated with water and stirred for 1 hour. The
precipitated solid was isolated by filtration, washed with water, and dried. This material
was suspended in diethyl ether (400 mL), sonicated, isolated by filtration, and then dried
in a vacuum oven at 40 °C for 16 hours to provide 58.1 g of l-[(7-bromo-3-
nitro[l,5]naphthyridin-4-yl)amino]-2-methylpropan-2-ol as a yellow solid, mp 189-190
15 °C.
PartB
A Parr vessel was charged with 5% platmurn on carbon (5.8 g) and a suspension of
l-[(7-bromo-3-m^o[l,5]naphthyridin-4-yl)amiri.o]-2-methylpropan-2-ol (58.00 g) in
acetonitrile (800 mL) and methanol (400 mL). The vessel was placed under hydrogen
20 pressure (30 psi, 2.1 X 10 5 Pa) for 8 hours. The reaction mixture was filtered through a
layer of CELITE filter aid. The filtrate was concentrated under reduced pressure to
provide 52.70 g of 1 -[(3-amino-7-bromo[ 1 ,5]naphthyridin-4-yl)amino]-2-methylpropan-2-
ol as a yellow solid.
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PartC
3-Methoxypropionyl chloride (24.90 g, 203 mmol) was added over a period of five
minutes to a mixture of l-[(3-amino-7-bromo[l,5]naphthyridiri-4-yl)amino]-2-
methylpropan-2-ol (52.70 g, 169 mmol), chloroform (100 mL), arid acetonitrile (530 mL).
5 The reaction mixture was stirred at room temperature overnight. The precipitated solid
was isolated by filtration, washed well with acetonitrile, and then dried to provide 60.10 g
of N- {7-bromo-4-[(2-hydroxy-2-methylpropyl)amino] [ 1 ,5]naphthyridin-3-yl} -3-
methoxypropionamide hydrochloride as a brown solid, mp 206-208 °C.
PartD
1 0 A mixture ofN- {7-bromo-4-[(2-hydroxy-2-methylpropyl)amino] [ 1 ,5]naphthyridin-
3-yl}-3-methoxypropionamide hydrochloride (60.00 g, 138 mmol), potassium carbonate
(60 g), water (300 mL), and ethanol (900 mL) was heated at reflux for 16 hours and then
concentrated under reduced pressure. The precipitated solid was isolated by filtration,
washed sequentially with water and methanol, and dried to provide a brown solid. This
1 5 material was dissolved in a 3/1 mixture of chloroform/methanol and decolorized with
activated charcoal to provide 38.5 g of l-[7-bromo-2-(2-methoxyethyl)-li/-imidazo[4,5-
c][l,5]naphthyridin-l-yl]-2-methylpropan-2-ol as a white solid, mp 125 °C. Anal, calcd
for Ci6Hi 9 BrN 4 0 2 : %C, 50.67; %H, 5.05; %N, 14.77; Found: %C y 50.86; %H 4.94; %N,
15.01.
20 Part E
mCPBA (34.77 g of 75% pure material, 151 mmol) was added to a solution of 1-
[7-bromo-2-(2-methoxyethyl)- l#-imidazo[4,5-c] [ 1 ,5]naphthyridin- 1 -yl] -2-methylpropan-
2-ol (38.2 g, 101 mmol) in dichloromethane (450 mL) and the reaction mixture was stirred
for 3 hours. The reaction mixture was diluted with dichloromethane (200 mL), washed
25 sequentially with 4% aqueous sodium carbonate (2 x 150 mL) and brine (1 x 150 mL), and
concentrated under reduced pressure to provide the N-oxide derivative. The TV-oxide
derivative was combined with dichloromethane (450 mL) and concentrated ammonium
hydroxide (200 mL) and the mixture was cooled in an ice bath. ^-Toluenesulfonyl
chloride (24 g) was added in portions. After the addition was complete the ice bath was
30 removed and the reaction mixture was stirred at ambient temperature for 1 6 hours. The
reaction mixture was diluted with dichloromethane (200 mL). Suspended solids were
isolated by filtration, washed with water, and dried to provide 7.60 g of l-[4-amino-7-
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bromo-2-(2-methoxyethyl)- li7-imidazo [4,5-c] [ 1 ,5]naphthyridin- 1 -yl] -2-methylp>ropan-2-
ol as an off white solid, mp 210-21 1 °C.
Anal. Calcd for C 16 H2oBrN 5 02: C, 48.74; H, 5.11; N, 17.76. Found: C, 48.63; H, 5.10; N,
17.80.
Examples 195 -239
The methods described in Examples 154-194 were followed using l-[4-amino-7-
bromo-2-(2-methoxyethyl)-l/f-imidazo[4,5-c][l,5]naphthyridin-l-yl]-2-methylpxopan-2-
ol (39.6 mg, 0.100 mmol) instead of l-(4-amino-7-bromo-2-ethyl-l//-imidazo[4 :> 5-
c][l,5]naphthyridin-l-yl)-2-methylpropan-2-ol with the modification that the samples
were not diluted in methanol after the initial heating at 80 °C overnight. The table below
shows the reagent added to each test tube, the structure of the resulting compound, and the
observed accurate mass for the isolated trifluoroacetate salt.
R A^N W-CH 3
R OH 3
Example
Reagent
R
Measured
Mass
(M+H)
None
Br^
394.0905
195
Furan-3-boronic acid
cr
382.1S80
196
Phenylboronic acid
Or
392.2085
197
Pyridine-3-boronic acid
N
393.2048
198
3-Methylphenylboronic acid
CH 3
406.2235
121
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199
4-Methylphenylboronic acid
406.2226
200
o-Tolylboronic acid
406.2256
201
3-Hydroxyphenylboronic acid
OH
408.2012
202
3-Cyanophenylboronic acid
N
417.2042
203
4-Cyanophenylboronic acid
417.2022
204
4-Vinylphenylboronic acid
CH 2
418.2255
205
^-Phenylethenylboronic acid
of
418.2242
206
3,5-Dimethylphenylboronic acid
V
CH 3
420.2391
207
4-Ethylphenylboronic acid
420.2406
208
2-Methoxyphenylboronic acid
GC
CH 3
422.2182
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209
4-Methoxyphenylboronic acid
xx
CH 3
422.2198
210
3-Aminophenylboronic acid
monohydrate
NH 2
407.2192
211
3-Chlorophenylboronic acid
426.1703
212
4-Chlorophenylboronic acid
XX
426.1657
213
2,4-Difluorophenylboronic acid
XX
428.1884
214
Benzo[Z?]furan-2-boronic acid
432.2018
215
3-Acetylphenylboronic acid
0 A CH 3
434.2191
216
4-Acetylphenylboronic acid
O
434.2188
217
(3-Aminocarbonylphenyl)-
boronic acid
O^NH 2
435.2119
218
3,4-
Methylenedioxyphenylboronic
acid
&
\~-o
436.1964
123
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219
2-Ethoxyphenylboronic acid
ex
^CH 3
436.2356
220
3-Ethoxyphenylboronic acid
(X
V
r°
CH 3
436.2342
221
4-(Methylthio)phenylboronic
acid
CH,
438.1961
222
2-Ethoxy-5-methylphenylboronic
acid
h . c yV
450.2529
223
2-Isopropoxyphenylboronic acid
H 3 C^CH 3
450.2491
224
4-Isopropoxyphenylboronic acid
H 3 C CH 3
450.2483
225
3,4-Dimethoxyphenylboronic
acid
°CH 3
452.2301
226
3 -(4-Boronophenyl)propionic
acid
XX
0
464.2289
124
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227
4-
(Methoxycarobonylamino)phenyl
boronic acid
CH 3
228
3-(Af-Isopropylaminocarbonyl)-
phenylboronic acid
or
x
HN^O
H,C CH,
477.2588
229
3 -(iV-Propylaminocarbonyl)-
phenylboronic acid
CH 3
477.2597
230
4-Borono-DZ-phenylalanine
HO y NH 2
0
479.2408
231
3,4,5-Trimethoxyphenylboronic
acid
CH 3
CH 3 O
°CH 3
482.2391
232
3 -(Butylaminocarbonyl)phenyl-
boronic acid
HN U
w 3 J^
491 2756
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233
3-(Isobutylaminocarbonyl)-
phenylboronic acid
5"
HN O
CH 3
491.2758
234
4-(Isol)u.tyl3iiiiiiocErl)otiyl)-
phenylboronic acid
H 3 C CH 3
491.2774
235
4-(Cyclopentylaminocarbonyl)-
phenylboronic acid
cr NH
503.2751
236
4-Benzyloxy-3-
fluorophenylboronic acid
516.2403
237
3 -(iV-B enzylaminocarbonyl)-
phenylboronic acid
HN O
&
238
(4-Aminomethylphenyl)boronic
acid Pinacol Ester, hydrochloride
421.2362
239
l-(Phenylsulfonyl)-l#-indol-3-
ylboronic acid
Q _
o
571.2127
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Examples 240 - 272
The methods described in Examples 154-194 were followed using l-[4-amino-7-
bromo-2-(2-methoxyethyl)- l//-imidazo[4,5-c] [ 1 ,5]naphthyridin-l -yl]-2-methylpropan-2-
ol (39.5 mg, 0.100 mmol) instead of l-(4-ammo-7-bromo-2-emyl-li/-imidazo[4,5-
5 c] [ 1 ,5]naphthyridin- 1 -yl)-2-methylpropan-2-ol. After the samples were heated overnight,
Example 241 was driven to completion by adding additional palladium (II) acetate (0.150
mL), heating for 30 minutes at 80 °C, adding pyridine-3-boronic acid (0.11 mmol) and
methanol (1 mL), and heating at 80 °C for 16 hours. After each sample was purified using
Waters Oasis Sample Extractions Cartridge MCX according to the method described in
10 Examples 4-58, and the resulting basic solution was concentrated by vacuum
centrifugation, the reaction with boron tribromide described in Examples 128-151 was
carried out using 0.400 mL of boron tribromide solution for each test tube. The
compounds were purified by reversed phase prep HPLC according to the method
described in Examples 77 - 127. The table below shows the reagent added to each test
15 tube, the structure of the resulting compound, and the observed accurate mass for the
isolated trifluoroacetate salt.
Examples 240 - 272
NH 2
R A^N WcH 3
R OH 3
Example
Reagent
R
Measured
Mass
(M+H)
240
Phenylboronic acid
a
378.1948
241
Pyridine-3-boronic acid
379.1908
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242
Pyridine-4-boronic acid
cx
379.1918
243
Thiophene-3-boronic acid
cr
384.1483
244
4-Methylphenylboronic acid
392.2052
245
3-Hydroxyphenylboronic acid
394.1910
246
3,5-Dimethylphenylboronic acid
H C. ^\ /
CH 3
406.2278
247
4-Ethylphenylboronic acid
406.2274
248
3-Chlorophenylboronic acid
412.1532
249
4-Chlorophenylboronic acid
Xf
412.1524
250
Benzo[6]furan-2-boronic acid
418.1891
251
(3-Aminocarbonylphenyl)-
boronic acid
O^NH 2
421.1974
252
4-(7Y,7Y-Dimethylamino)phenyl-
boronic acid
H 3 C... Ji^J
3 N
CH 3
421.2391
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253
2-Ethoxy-5-
methylphenylfaoronic acid
408.2050
254
3,4-Dichlorophenylboronic acid
CI
446.1184
255
3-(4-Boronophenyl)propionic
acid
XX
"°X
o
450.2180
256
3-(7V~Isopropylsiniiiocs,rl)onyl)-
phenylboronic acid
HN^O
H 3 C^CH 3
463.2501
257
3 -(A^Propylaminocarbonyl)-
phenylboronic acid
HN^O
CH 3
463.2482
258
4-Borono-Z)Z-phenylalanine
O
465.2278
259
4-(Ethylsulfonyl)phenylboronic
acid
»^,XX
470.1879
260
3-(Methylsulfbnylamino)-
phenylboronic acid
(X
x^
0,_.NH
H 3 C '6
471.1835
129
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261
4-(Methylsulfonylamino)-
phenylboronic acid
fY
471.1864
262
3-(2-Cyanoethylaminocarbonyl>
phenylboronic acid
HN 0
N
474.2297
263
3-(Pyrrolidine-l-
carbonyl)phenylboronic acid
I
O 0
475.2468
264
4-(Pyrrolidine-l-
carbonyl)phenylboronic acid
475.2480
265
3-(Butylaminocai-bonyl)-
phenylboronic acid
9"
HN O
J
477.2648
266
4-(Isobutylaminocarbonyl)-
phenylboronic acid
1
.NH
H 3 C CH 3
477.2640
130
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267
3 -(Piperidine- 1 -
carbonyl)phenylboronic acid
or
G
489.2656
268
4-(Cyclopentylaminocarbonyl)-
phenylboronic acid
oXX
a"
489.2626
269
4-(Morpholine-4-
carbonyl)phenylboronic acid
T
0
491.2423
3 -(N-B enzylaminocarbonyl)-
phenylboronic acid
HN^O^
^1 1 947R
Jil .^*T / O
271
(4-Aminomethylphenyl)boronic
acid pinacol ester, hydrochloride
407.2218
272
1 -(Phenylsulfonyl)-lH-indol-3-
ylboronic acid
Q _
O
557.2020
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Preparation of l-{[4-Amino-7-bromo-2-(ethoxymethyl)-li^-imidazo[4,5-
c] [ 1 ,5]naphthyridin- 1 -yl]methyl} cyclopentanol
NH,
Part A
To a solution of cyclopentanone (40.0 mL, 452 mmol) in nitromethane (36 mL)
and ethanol (14 mL) was added a solution of sodium ethoxide in ethanol (2.67 M, 8.5 mL,
23 mmol). The solution was stirred for five days at room temperature. Water (400 mL)
was added, and the mixture was extracted with ethyl acetate (2 x 350 mL). The combined
organic extracts were washed with water (2 x 200 mL) and brine (200 mL), dried over
magnesium sulfate, filtered, and concentrated under reduced pressure. The starting
materials and solvent were removed from the product by distillation under reduced
pressure to yield 8.3 g of l-(nitromethyl)cyclopentanol as a yellow liquid.
PartB
A mixture of l-(nitromethyl)cyclopentanol (8.3 g, 57 mmol) and 20% palladium
hydroxide on carbon (0.6 g) in ethanol (150 mL) was hydrogenated at 35 psi (2.4 x 10 5 Pa)
on a Parr apparatus for one day. After workup, the reaction was not complete and was
subjected to the reaction conditions again for eight days using fresh catalyst- The mixture
was filtered through CELITE filter agent and the filtrate was concentrated to yield an oil
that contained a 13:1 ratio of the desired amine product, l-(aminomethyl)cyclopentanol, to
the corresponding hydroxylamine. The oil was concentrated from toluene. Material from
a separate run was used in the next step.
PartC
A suspension of 7-bromo-4-chloro-3-nitro[l,5]naphthyridine (54.42 g, 188.6
mmol) in chloroform (820 mL) was cooled to 0 °C, and triethylamine (105 rnL, 755
mmol) was added. A solution of l-(aminomethyl)cyclopentanol (28.25 g, 245.2 mmol) in
chloroform (272 mL) was added slowly over a period of 15 minutes. The reaction was
allowed to warm to room temperature and stirred for 30 minutes. The solution was
washed sequentially with water (500 mL) and saturated aqueous sodium bicarbonate (750
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mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to
provide l-{[(7-bromo-3-nitro[l,5]naphthyrid^-4-yl)amino]methyl}cyclopentanol.
PartD
The material from Part C was dissolved in acetonitrile (1 .66 L) and isopropyl
5 alcohol (496 mL) and added to a Parr vessel. Catalytic 5% platinum on carbon (6.6 g) was
added, and the reaction mixture was placed under hydrogen pressure for three days and
filtered through a layer of CELITE filter agent. The filtrate was concentrated under
reduced pressure to provide l-{[(3-amino-7-bromo[l,5]naphthyridin-4-
yl)amino]methyl} cyclopentanol.
10 PartE
Ethoxyacetyl chloride (25.4 g, 207 mmol) was added to a mixture of the material
from Part D and acetonitrile (1.27 L). The reaction was stirred at room temperature, and
over the course of two hours, additional ethoxyacetyl chloride (20.8 g, 0.170 mol) was
added. The solvent was removed under reduced pressure to provide 7Y-(7-bromo-4- {[(1-
15 hydroxycyclopentyl)methyl]amino}[l,5]naphthyridin-3-yl)-2-ethoxyacetamide
hydrochloride.
PartF
Triethylamine (38 mL, 270 mmol) was added to a suspension of the material from
Part E in ethanol (380 mL), and the resulting solution was heated at reflux (85 °C) for
20 seven hours, allowed to cool to room temperature, and stirred overnight. The volatiles
were removed under reduced pressure, and the residue was partitioned between
chloroform (800 mL) and water (200 mL). The organic layer was separated, washed with
brine (2 x 300 mL), dried over sodium sulfate, and concentrated under reduced pressure to
provide l-{[7-bromo-2-(ethoxymethyl)4fl-imidazo[4,5-c][l,5]naphthyridin-l-
25 yljmethyl} cyclopentanol as a brown solid.
PartG
mCBPA (21 g of about 50% pure material, 61 mmol) was added to a solution of 1-
{ [7-bromo-2-(ethoxymethyl)- l#-imidazo[4,5-c] [1 ,5]naphthyridin- 1 -
yl]methyl} cyclopentanol (18.89 g, 46.6 mmol) in chloroform (190 mL), and the reaction
30 was stirred for one hour at room temperature. Additional mCPBA (1 1 g) was added, and
the reaction was stirred for an additional 30 minutes. Concentrated ammonium hydroxide
(40 mL) was added slowly followed by ^-toluenesulfonyl chloride (9.32 g, 48.9 mmol).
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The reaction was stirred for one hour at room temperature, and additional chloroform (600
mL) was added. The reaction was stirred for one additional hour, and additional p-
toluenesulfonyl chloride (4.45 g, 23.3 mmol) and ammonium hydroxide (10 mL) were
added. After the reaction mixture was stirred for an additional 1.5 hours, it was filtered to
5 remove a precipitate. The filtrate layers were separated, and the organic phase was
washed with saturated aqueous sodium bicarbonate (2 x 200 mL), dried over sodium
sulfate, and concentrated under reduced pressure. The residue (25.86 g) was triturated
with acetonitrile at 98 °C, and a solid impurity was removed by filtration. The acetonitrile
was removed under reduced pressure, and the residue was dissolved in chloroform. The
10 resulting solution was washed with 1% aqueous sodium carbonate, dried over sodium
sulfate, filtered, and concentrated under reduced pressure. The residue was purified by
column chromatography on silica gel (eluting with 98.5:1.5 chloroform:methanol) and
then triturated with acetonitrile at 98 °C, isolated by filtration at room temperature, and
dried in a vacuum oven at 1 10 °C over two nights to provide 4.83 g of l-{[4-amino-7-
1 5 bromo-2-(ethoxymethyl)- l#-imidazo [4,5-c] [ 1 ,5]naphthyridin- 1 -yl]methyl} cyclopentanol
as a white solid, mp 166-167.5 °C.
Anal, calcd for Ci 8 H2 2 BrN 5 0 2 : C, 51.44; H, 5.28; N, 16.66. Found: C, 51.32; H, 5.24; N,
16.63.
20 Example 273
l-{[4-Ainino-2-(ethoxymethyl)-7-(4-fluorophenyl)-li/-imidazo[4,5-c][l,5]naphthyridin-l-
yl]methyl} cyclopentanol
1 - { [4-Amino-7-bromo-2-(ethoxymethyl)-lif-imidazo[4,5-c] [ 1 ,5]naphthyridin- 1 -
25 yl]methyl} cyclopentanol (1.13 g, 2.7 mmol), 4-fluorobenzeneboronic acid (0.43 g, 3.1
mmol), triphenylphosphine (6.3 mg, 0.024 mmol), and 5:1 (v/v) 1-propanol/water (6.6
mL) were combined under a nitrogen atmosphere. A 5 mg/mL solution of palladium (II)
acetate (1.8 mg, 0.008 mmol) in toluene and aqueous sodium carbonate (1.8 mL of 2 M)
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were sequentially added. The reaction mixture was heated at reflux for two hours, allowed
to cool to room temperature, and partitioned between chloroform (75 mL) and brine (20
mL). The organic fraction was separated, dried over sodium sulfate, filtered, and
concentrated under reduced pressure. The residue (1.27 g) was purified by trituration with
5 acetonitrile at 98 °C followed by recrystallization from chloroform/hexane. The crystals
were dried in a vacuum oven at 1 10 °C for two hours to provide 0.67 g of l-{[4-amino-2-
(ethoxymethyl)-7<4-fluorophenyl)-li/-imidazo[4,5-c][l,5]naphthyridin-l-
yl]methyl}cyclopentanol as a steel-gray solid, mp 212-212.5°C.
MS (APCI) m/z 436 (M + H) + ;
10 Anal, calcd for C24H26FN5O2: C, 66.19; H, 6.02; N, 16.08. Found: C, 66.16; H, 5.82; N,
16.09.
Examples 274-318
The methods described in Examples 154-194 were followed using l-{[4-amino-
1 5 2-(ethoxymethyl)-7-(4-fluorophenyl)- l#-imidazo[4,5-c] [1 ,5]naphthyridin- 1 -
yl]methyl}cyclopentanol (42 mg, 0.10 mmol) instead of l-(4-amino-7~bromo-2-ethyl-l#-
imidazo[4,5-c][l,5]naphthyridin-l-yl)-2-methylpropan-2-ol with the modification that the
samples were not diluted in methanol after the initial heating at 80 °C overnight. After
Example 318 was heated, it was treated with glacial acetic acid (0.500 mL) in deionized
20 water (0.500 mL) and tetrahydrofuran (THF) (0.500 mL) and heated at 60 °C for four
hours before the purification procedures. The table below shows the reagent added to each
test tube, the structure of the resulting compound, and the observed accurate mass for the
isolated trifluoroacetate salt.
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Examples 274-318
NH ^, ,
I 2 CH 3
K OH
Example
Reagent
R
Measured
Mass
(M+H)
None
420.1010
274
Furan-3-boronic acid
or
408.2018
275
Phenylboronic acid
CX
418.2246
276
Pyridine-3-boronic acid
Cf
419.2180
277
3-Methylphenylboronic acid
CX
CH
432.2399
278
4-Methylphenylboronic acid
432.2399
279
o-Tolylboronic acid
432.2370
280
2-Hydroxyphenylboronic
acid
cc
434.2184
281
3 -Hydroxyphenylboronic
acid
CX
OH
434.2200
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282
4-Vinylphenylboronic acid
xr
CH 2
444.2399
283
3,5-Dimethylphenylboronic
acid
CH 3
446.2534
284
4-Ethylphenylboronic acid
446.2546
285
2-Methoxyphenylboronic
acid
CH 3
448.2359
286
4-Methoxyphenylboronic
acid
CH 3
448.2319
287
(4-Fluoro-2-
hydroxy)phenylboronic acid
f^OCh
452.2119
288
3-Chlorophenylboronic acid
CI
452.1844
289
2-Chlorophenylboronic acid
oc
452.1846
290
4-Chlorophenylboronic acid
XX
452.1821
291
2,4-Difluorophenylboronic
acid
XX
454.2068
292
Benzo[&]furan-2-boronic acid
458.2165
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293
3-Acetylphenylboronic acid
O^CH 3
460.2357
294
(3 - Aminocarbonylphenyl)-
boronic acid
O^NH 2
461.2298
295
3 ,4-Methylenedioxyphenyl-
boronic acid
&
\-o
462.2112
296
4-(Methylthio)phenylboronic
acid
CH 3
464.2138
297
3-Aminophenylboronic acid
monohydrate
433.2337
298
2-Isopropoxyphenylboronic
acid
QC
H 3 C^CH 3
476.2664
299
4-Isopropoxyphenylboronic
acid
H 3 C^CH 3
476.2672
300
2,4-Dimethoxyphenyl-
boronic acid
CH 3 CH 3
478.2456
301
3 ,4-Dimethoxyphenylboronic
acid
°CH 3
478.2443
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302
(3 - Aminomethylphenyl)-
boronic acid, hydrochloride
H 2 N
447.2491
303
3 ,4-Dichlorophenylboronic
acid
CI
486.1453
304
4-(Methoxycarbonylamino)-
phenylboronic acid
A
CH,
491.2386
305
3-(iV-
Isopropylaminocarbonyl)-
phenylboronic acid
Cf
H 3 C CH 3
503.2766
306
3-(JV-
Propylaminocarbonyl)phenyl
boronic acid
HN-^O
CH 3
cri'J 978fi
JKjj.A 1 oO
307
4-Borono-DL-phenylalanine
XX
H0 Y^NH 2
0
505.2545
308
3,4,5-
Trimethoxyphenylboronic
acid
PH,
6H ' ° ch 3
508.2562
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309
4-
(Ethylsulfonyl)phenylboronic
acid
510.2166
310
3-
(Methylsulfonylamino)phenyl
boronic acid
(T
V
0,_.NH
H 3 C 6
511.2104
3 -(Butylaminocarbonyl)-
phenylboronic acid
HN U
H 3 C J
517.2953
312
3-(Isobutylaminocarbonyl)-
phenylboronic acid
HN^O
H 3 C r J
CH 3
517.2916
313
4 - (Is obut ^lsmino c 3xb ony 1)-
phenylboronic acid
T
.NH
H 3 C CH 3
517.2930
314
3-(Piperidine-l-
carbonyl)phenylboronic acid
I
G
529.2957
315
4-
(Cyclopentylaminocarbonyl)-
phenylboronic acid
529.2908
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316
3-
(Furfurylaminocarbonyl)phen
ylboronic acid
7
HN O
C A 1 O COO
317
4-Benzyloxy-3-
fluorophenylboronic acid
542.2554
318
5-{tert-
butyldimethylsilanyloxy-
methyl)pyridine-3-boronic
acid
HO^jj^Y^
N
449.2278
Examples 319 -330
The methods described in Examples 154 - 194 were followed using l-{[4-amino-
2-(ethoxymethyl)-7-(4-fluorophenyl)-l//'-imidazo[4,5-c][l,5]naphthyridin-l-
5 yl]methyl}cyclopentanol (42 mg, 0. 10 mmol) instead of l-(4-amino-7-bromo-2-e1hyl-l#'-
imidazo[4,5-c][l,5]naphthyridin-l-yl)-2-methylpropan-2-ol with the modification that the
samples were not diluted in methanol after the initial heating at 80 °C overnight. After
each sample was purified using Waters Oasis Sample Extractions Cartridge MCX
according to the method described in Examples 4 - 58, and the resulting basic solution
1 0 was concentrated by vacuum centrifugation, the reaction with boron tribromide described
in Examples 128 - 151 was carried out using 0.400 mL of boron tribromide solution for
each test tube. The compounds were purified by reversed phase prep HPLC according to
the method described in Examples 77 - 127. The table below shows the reagent added to
each test tube, the structure of the resulting compound, and the observed accurate mass for
1 5 the isolated trifluoroacetate salt.
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Example 319- 330
NH
K OH
Example
Reagent
R
Measured
Mass
(M+H)
None
392.0712
319
Phenylboronic acid
cx
390.1926
320
2-Hydroxyphenylboronic acid
OCh
406.1866
321
3-Hydroxyphenylboronic acid
cx
OH
406.1866
322
3-Chlorophenylboronic acid
424.1538
323
2-Chlorophenylboronic acid
cx
424.1515
324
4-Chlorophenylboronic acid
oXX
424.1515
325
3,4-Dichlorophenylboronic
acid
CI
458.1111
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326
3-(N-
Isopropylaminocarbonyl)-
phenylboronic acid
cr
HN^O
H 3 C^CH 3
475.2462
327
3-(7V^Propylaminocarbonyl)-
phenylboronic acid
HN^O
CH,
AHZ n A AC
328
4-
(Ethylsulfonyl)phenylboronic
acid
482.1849
329
3 -(Methylsulfonylamino)-
phenylboronic acid
y
0, q .NH
H a c '6
483.1805
330
3 -(Piperidine- 1 -
carbonyl)phenylboronic acid
cr
o °
501.2579
Preparation of A/"-{2-[4-Amino-7-bromo-2-(ethoxymethyl)-l/7-iniidazo[4,5-
c] [ 1 ,5]naphthyridin- 1 -yl]-l , 1 -dimethylethyl}methanesulfonamide
Part A
A modification of the method described in Part A of the preparation of l-[4-amino-
7-bromo-2-(ethoxymethyl)- lif-imidazo[4,5-c] [ 1 ,5]naphthyridin- 1 -yl]-2-methylpropan-2-
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ol was followed using 150 g (0.42 mol) of 7-bromo-4-chloro-3-nitro[l,5]naphthyridine
and l,2-diamino-2-methylpropane (80.7 g, 0.915 mol) in lieu of l-amino-2-methydpropan-
2-ol. The reaction was at 3 °C at the start of the addition of the diamine. Following the
addition, the reaction was stirred for 4.5 hours before it was concentrated under reduced
5 pressure. N- 1 -(7-Bromo-3 -nitro[ 1 ,5]naphthyridin-4-yl)-2-methylpropane- 1 ,2-diamine
(140 g) was obtained after drying over two nights in a vacuum oven at 35 °C.
PartB
A solution of sodium hydroxide (1 1.8 g, ) in deionized water (295 mL) was added
dropwise to a solution of A^l-(7-bromo-3-nitro[l,5]naphthyridin-4-yl)-2-methylpTopane-
10 1,2-diamine (100.0 g, 294.0 mmol) in tetrahydrofuran (1.3 L). A solution of di-fe/t-butyl
dicarbonate (72.8 g, 333 mmol) in THF (219 mL) was added slowly over a period of 25
minutes. The reaction was stirred at room temperature for three days. The THF was
removed under reduced pressure, and the resulting mixture was diluted with deionized
water (1 L) and extracted twice with dichloromethane (1.5 L). The combined extracts
15 were washed sequentially with saturated aqueous sodium carbonate (2 x 900 mL) and
brine (250 mL), dried over magnesium sulfate, filtered, and concentrated under reduced
pressure to provide 141 g of tert-butyl 2-[(7-bromo-3-nitro[l,5]naphthyrdin-4-yl)amino]-
1 , 1 -dimethylethylcarbamate.
PartC
20 A modification of the method described in Part B of the preparation of 1 - Q4-amino-
7-bromo-2-(ethoxymethyl)- 1 //-imidazo [4,5-c] [ 1 ,5]naphthyridin- 1 -yl] -2-methylpropan-2-
ol was used to reduce tert-butyl 2-[(7-bromo-3-nitro[l,5]naphthyrdin-4-yl)amino1-l,l-
dimethylethylcarbamate (138.0 g, 313.4 mmol). The reaction was placed under hydrogen
pressure for 5.5 hours. The reaction yielded 128 g of tert-butyl 2-[(3-amino-7-
25 bromo[l,5]naphthyrdin-4-yl)amino]-l,l-dimethylethylcarbamate containing some
acetonitrile.
PartD
The method described in Part C of the preparation of l-[4-amino-7-bromo-2-
(ethoxymethyl)4i7-imidazo[4,5-c][l,5]naphthyridin-lyl]-2-methylpropan-2-ol was used
30 to treat tert-butyl 2-[(3-amino-7-bromo[l,5]naphthyrdin-4-yl)amino]-l,l-
dimethylethylcarbamate (64.0 g, 0.156 mol) with ethoxyacetyl chloride (21.0 g, 0.171
mol) in acetonitrile (640 mL). At the completion of the reaction, additional acetonitrile
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(200 mL) was added, and the solid product was isolated by filtration, washed with a small
volume of acetonitrile, and dried for four hours to provide 55.6 g of tert-butyl 2-({7-
bromo-3-[(ethoxyacetyl)amino][l,5]naphthyrdin-4-yl}amino)-l,l-dimethylethylcarbamate
hydrochloride.
5 PartE
A modification of the method described in Part D of the preparation of l-[4-amino-
7-bromo-2-(ethoxymethyl)- l//-imidazo[4,5-c] [ 1 ,5]naphthyridin- 1 -yl] -2-methylpropan-2-
ol was used to treat tert-butyl 2-({7-bromo-3-[(ethoxyacetyl)amino][l,5]naphthyrdin-4-
yl} amino)- 1,1-dimethylethylcarbamate (55.6 g, 0.104 mol) with potassium carbonate
10 (55.6 g). After the ethanol was removed under reduced pressure, and the resulting mixture
was extracted with dichloromethane (4 x 300 mL). The combined extracts were
concentrated under reduced pressure to provide 51 g of tert-butyl {2-[7-bromo-2-
(ethoxymethyl)- l#-imidazo[4,5-c] [ 1 ,5]naphthyridin- 1 -yl]- 1 , 1 -dimethylethyl} carbamate as
a yellowish brown solid.
15 PartF
A modification of the method described in Part B of the preparation of l-(4-amino-
7-bromo-2-ethyl- lf/-imidazo[4,5-c] [ 1 ,5]naphthyridin- 1 -yl)-2-methylpropan-2-ol was used
to treat the material from Part E above with mCPBA (37.52 g of 75%, 163.1 mmol) in
dichloromethane (800 mL) followed by ammonium hydroxide (200 mL) mdp-
20 toluenesulfonyl chloride (25.90 g, 135.9 mmol) in dichloromethane (450 mL). After the
reaction was complete and diluted with dichloromethane (200 mL), it was washed with 4N
aqueous sodium carbonate (2 x 200 mL). The combined aqueous fractions were washed
extracted with dichloromethane (200 mL), and the combined organic fractions were
washed with brine, dried over sodium sulfated, filtered, and concentrated under reduced
25 pressure. The residue was triturated with acetonitrile to provide 1 8.77 g of tert-butyl {2-
[4-amino-7-bromo-2-(ethoxymethyl)- l#-imidazo[4,5-c] [ 1 ,5]naphthyridin- 1 -yl]- 1 , 1 -
dimethylethyl} carbamate as an off-white solid. A portion was recrystallized from
acetonitrile to provide the following analytical data, mp 176-178 °C.
Anal, calcd for C 2 iH 29 BrN 6 03: C, 51.12; H, 5.92; N, 17.03. Found: C, 51.07; H, 5.92; N,
30 17.09.
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PartG
Hydrogen chloride (56.74 g of a 2.2 M solution in ethanol, 124.8 mmol) was added
to a suspension of tert-butyl {2^4-amino-7-bromo-2-(ethoxymethyl)-lif-imidazo[4,5-
c][l,5]naphthyridin-l-yl]44-dimetiiylethyl}carbamate (15.40 g, 31.21 mmol) in
5 anhydrous ethanol (120 mL), and the reaction mixture was heated at reflux for four hours
and allowed to cool to room temperature. A precipitate had formed and was isolated by
filtration, washed with a small volume of cold ethanol, and dried in a vacuum oven at 60
°C to provide 12.26 g of l-(2-amino-2-methylpropyl)-7-bromo-2-(ethoxymethyl)-l//-
imidazo[4,5-c] [ 1 ,5]naphthyridin-4-amine dihydrochloride.
10 PartH
Triethylamine (13.02 g, 128.7 mmol) was added to a suspension of l-(2-amino-2-
methylpropyl)-7-bromo-2-(ethoxymethyl)-li7-imidazo[4,5-c][l,5]naphthyridin-4-amine
dihydrochloride (6.00 g, 12.9 mmol) in dichloromethane (500 mL), and the reaction was
cooled to 4 °C. A solution of methanesulfonyl chloride (1 .62 g, 14.2 mmol) in
1 5 dichloromethane (10 mL) was then added dropwise. The reaction mixture was allowed to
warm to room temperature, stirred for 24 hours, diluted with dichloromethane (200 mL),
washed sequentially with water (200 mL), 4% aqueous sodium carbonate (2 x 200 mL),
water (200 mL), and brine (200 mL), and concentrated under reduced pressure. The crude
product was purified by automated flash chromatography (FLASH 40+M silica cartridge,
20 eluting with 0 to 25% CMA in chloroform) followed by recrystallization from acetonitrile
to provide 5.21 g of 7V-{2-[4-amino-7-bromo-2-(ethoxymethyl)-li/-imidazo[4,5-
c][l,5]naphthyridin-l-yl]-l,l-dimethylethyl}methanesulfonamide as a white solid, 211-
212 °C.
Anal, calcd for CnH^BrNeOsS: C, 43.32; H, 4.92; N, 17.83. Found: C, 43.35; H, 4.85;
25 N, 18.07.
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Example 331
A^2- {4-Amino-2-(ethoxymethyl>^
c] [ 1 , 5 ]naphthyridin- 1 -yl} - 1 , 1 -dimethylethyl)methanesulfonamide
5 The method described in Example 1 52 was used to treat N- {2-[4-amino-7-bromo-
2-(ethoxymethyl)- li/-imidazo[4,5-e] [ 1 ,5]naphthyridin- 1 -yl]- 1 , 1 -
dimethylethyl}methanesulfonamide (1.2 g, 2.55 mmol) and 3-
(hydroxymethyl)benzeneboronic acid (0.58 g, 3.8 mmol) in 1-propanol (15 mL) with
triphenylphosphine (20.0 mg, 0.0760 mmol), aqueous sodium carbonate (3.82 mL of 2 M),
10 water (3 mL), and palladium (II) acetate (5.7 mg, 0.025 mmol) with the following
modifications. The reaction mixture was heated at reflux overnight. The crude product
was purified by automated flash chromatography (FLASH 40+M cartridge, eluting with
0% to 35% CMA in chloroform) followed by recrystallization from acetonitrile to provide
0.98 gofA^-(2-{4-mnino-2-(ethoxymethyl)-7-[3-(hydroxymethyl)phenyl]-l//-imidazo[4,5-
15 c][l,5]naphthyridin-l-yl}-l,l-dimethylethyl)methanesulfonamide as a white solid, mp
173-174 °C.
MS (APCI) m/z 499.33 (M + H) + ;
Anal. Calcd for C24H30N6O4S: C, 57.81; H, 6.06; N, 16.85. Found: C, 57.67; H, 5.80; N,
16.90.
20
Examples 332 - 336
iV-{2-[4-Amino-7-bromo-2-(ethoxymethyl)-li/-imidazo[4,5-c][l,5]naphmyridin-l-
yl]-l,l-dimethylethyl}methanesulfonamide (0.100 g, 0.21 mmol) was added to a test tube.
The boronic acid (0.22 mmol) indicated in the table below and rc-propanol (3.2 mL) were
25 sequentially added. The test tube was purged with nitrogen. Palladium (II) acetate (0.300
mL of a 4 mg/mL solution in toluene, 0.0053 mmol), 2M aqueous sodium carbonate
solution (1.2 mL), deionized water (226 uL), and a solution of 0.15 mol%
triphenylphosphine in rc-propanol (106 uL, 0.016 mmol) were sequentially added. The
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test tube was purged with nitrogen, capped, and then heated at 80 °C for four hours in a
sand bath.
The contents of each test tube were passed through a Waters Oasis Sample
Extractions Cartridge MCX (6 cc) according to the procedure described in Examples 4 -
5 58. The resulting basic solutions were concentrated by vacuum centrifugation. Half of the
material from each tube was purified by reversed phase prep HPLC according to the
method described in Examples 77 - 127. The other half of the material was used in
Examples 337 - 338. The table below shows the reagent added to each test tube, the
structure of the resulting compound, and the observed accurate mass for the isolated
10 trifluoroacetate salt.
Example 332 - 336
NH 2 CH 3
1/N M^ CH 3
Example
Reagent
R
Measured
Mass (M+H)
None
471.0826
332
Phenylboronic acid
cr
469.2024
333
Pyridine-3-boronic acid
470.1975
334
Thiophene-3-boronic acid
475.1560
335
4-(Hydroxymethyl)-
phenylboronic acid
499.2130
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336
3-Chlorophenylboronic
503.1670
acid
Example 337 - 338
The reserved material from Examples 332-336 was subjected to the reaction with
5 boron tribromide described in Examples 128 - 151 using 0.400 mL of boron tribromide
solution for each test tube. After each reaction was stirred for four hours at room
temperature, additional boron tribromide (0.200 mL of 1 M in dichloromethane) was
added. The reaction was stirred for one hour at room temperature and allowed to stand for
65 hours. Methanol (1 mL) and 6 N hydrochloric acid (0.500 mL) were added to each
1 0 tube. The contents were vortexed for 30 minutes, and the volatiles were removed by
vacuum centrifugation. The compounds were purified by reversed phase prep HPLC
according to the method described in Examples 77 - 127. The table below shows the
reagent added to each test tube, the structure of the resulting compound, and the observed
accurate mass for the isolated trifluoroacetate salt.
15
Examples 337-338
NH 2
N OH
N C H 3
Example
Reagent
R
Measured Mass (M+H)
337
Pyridine-3-boronic acid
442.1650
338
3 -Chlorophenylboronic
acid
475.1310
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Preparation of 7-Bromo-2-(emoxymethyl)-l-(2-fluoro-2^
c] [ 1 ,5]naphthyridin-4-amine
Part A
5 A solution of tert-butyl 2-hydroxy-2-methylpropylcarbamate (19.2 g, 101 mmol) in
dichloromethane (500 mL) was stirred at -78 °C under a nitrogen atmosphere, and
(diethylamino)sulfur trifluoride (DAST) (18.0 g, 1 12 mmol) was added dropwise. The
solution was allowed to warm to room temperature and stirred overnight. Saturated
aqueous sodium bicarbonate (150 mL) was added. The organic layer was then separated
1 0 and washed sequentially with saturated aqueous sodium bicarbonate (150 mL), water (150
mL), and brine (150 mL); dried over magnesium sulfate; filtered; and concentrated under
reduced pressure. The resulting oil was purified by automated flash chromatography
(FLASH 651 cartridge, eluting with 10% ethyl acetate in hexane) to provide 13.7 g of tert-
butyl 2-fluoro-2-methylpropylcarbamate as a light yellow oil that crystallized overnight.
15 PartB
Hydrogen chloride (50 mL of a 4 M solution in 1,4-dioxane) was added to a
solution of tert-butyl 2-fluoro-2-methylpropylcarbamate (13.7 g, 71.6 mmol) in
dichloromethane (300 mL), and the reaction was stirred for five hours at room temperature
and concentrated under reduced pressure. The residue was three times dissolved in
20 toluene and concentrated under reduced pressure to provide 8.08 g of 2-fluoro-2-
methylpropan-1 -amine hydrochloride as a white solid.
PartC
Triethylamine (17.3 g, 171 mmol) was added to a suspension of 7-bromo-4-chloro-
3-nitro[l,5]naphthyridine (52.2 mmol) inDMF (50 mL), and then a solution of 2-fluoro-2-
25 methylpropan-1 -amine hydrochloride (5.46 g, 42.8 mmol) in DMF (25 mL) was added
dropwise over a period often minutes. The reaction mixture was stirred at room
temperature for 14.5 hours, and water (500 mL) was added. The resulting mixture was
stirred for one hour. A solid was present and was isolated by filtration, washed with
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water, and dried overnight in a vacuum oven at 65 °C to provide 14.7 g of 7-bromo-iV-(2-
fluoro-2-raethylpropyl)-3-nitro[l,5]naphthyridin-4-amine as a reddish-brown solid.
PartD
A Parr vessel was charged with 5% platinum on carbon (700 mg), 7-bromo-iV-(2-
5 fluoro-2-methylpropyl)-3-nitro[l ,5]naphmyridin-4-amine (7.00 g, 20.4 mmol), and
acetonitrile (50 mL) and placed under hydrogen pressure (30 psi, 2.1 X 10 5 Pa) for two
hours. The reaction mixture was filtered through a layer of CELITE filter aid. The filter
cake was washed with acetonitrile. The filtrate was concentrated under reduced pressure
to provide 6.22 g of 7-bromo- J A/-(2-fluoro-2-methylpropyl)[l,5]naphthyridin-3,4-diamine
10 as a dark brown oil.
PartE
Ethoxyacetyl chloride (2.7 g, 22 mmol) was added dropwise to a solution of 7-
bromo-iV-(2-fluoro-2-methylpropyl)[l,5]naphthyridin-3,4-diamine (6.2 g, 19.8 mmol) in
acetonitrile (65 mL). The reaction was stirred for 20 minutes at room temperature and
1 5 concentrated under reduced pressure. The residue was treated with potassium carbonate
(4.1 g, 29.7 mmol) in ethanol (90 mL) and water (30 mL) according to the method
described in Part D of the preparation of l-[4-amino-7-bromo-2-(ethoxymethyl)-li/-
imidazo[4,5-c][l,5]naphthyridin-l-yl]-2-methylpropan-2-ol with the modification that the
reaction was stirred at room temperature for 19 hours and then heated at reflux for five
20 hours. After the drying step 6.65 g of product were obtained. A portion of the isolated
product (0.5 g) was purified by automated flash chromatography (40+M silica cartridge,
eluting with 3% to 10% methanol in dichloromethane) followed by recrystallization from
acetonitrile. The crystals were isolated by filtration, washed with cold acetonitrile, and
dried in a vacuum oven at 65 °C to provide 21 mg of analytically pure 7-bromo-2-
25 (ethoxymethyl)-l-(2-fluoro-2-methylpropyl)-li^-imidazo[4,5-c][l,5]naphthyridineas
white needles, mp 127-128 °C.
Anal. Calcd for Ci 6 Hi 8 BrFN 4 0: C, 50.41; H, 4.76; N, 14.70. Found: C, 50.42; H, 4.73;
N, 14.78.
PartF
3 0 mCPBA (5 .4 g of 77% purity, 24 mmol) was added to a stirred solution of 7-
bromo-2-(ethoxymethyl)-l-(2-fluoro-2-methylpropyl)-li/-imidazo[4,5-
c][l,5]naphthyridine (6.1 g, 16 mmol) in chloroform (160 mL), and the reaction was
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stirred at room temperature for 17.5 hours. Concentrated ammonium hydroxide (80 mL)
was added, and then p-toluenesulfonyl chloride (3.7 g, 19.2 mmol) was added over a
period of five minutes. The reaction mixture was stirred at room temperature for 1.5
hours, and an analysis by LC/MS indicated the presence of starting material. Additional
5 /j-toluenesulfonyl chloride (3.7 g) was added, and the reaction mixture was stirred at room
temperature for three hours. The aqueous layer was separated and extracted with
dichloromethane (3 x 10O mL). The combined organic fractions were dried over
magnesium sulfate, filtered, and concentrated under reduced pressure. The residue (14.5
g) was triturated with dichloromethane (50 mL), isolated by filtration, and washed with
1 0 dichloromethane to provide 970 mg of desired product. The filtrate was concentrated
under reduced pressure, and the residue was triturated with methanol, isolated by filtration,
washed with methanol, and dried in a vacuum oven at 65 °C for five hours to provide an
additional 2.45 g of product. Silica gel was added to the filtrate. The mixture was
concentrated under reduced pressure and purified by automated flash chromatography
15 (FLASH 651 cartridge, eluting with 3% to 10% methanol in ethyl acetate) to provide 530
mg of product. A portion of the isolated material (220 mg) was recrystallized from
acetonitrile (50 mL). The crystals were isolated by filtration, washed with acetonitrile,
and dried in a vacuum oven at 80 °C to provide 92 mg of analytically pure 7-bromo-2-
(ethoxymethyl)- 1 -(2-fluoro-2-methylpropyl)- lH-imidazo [4,5-c] [ 1 ,5]naphthyridin-4-amine
20 as a light yellow solid, irip 22 1 -222 °C.
Anal. Calcd for Ci 6 Hi 9 BrFN 5 0: C, 48.50; H, 4.83; N, 17.67. Found: C, 48.60; H, 4.69;
N, 17.64.
Examples 339 - 342
25 Under a nitrogen atmosphere, a suspension of 7-bromo-2-(ethoxymethyl)- 1 -(2-
fluoro-2-methylpropyl)-li/-imidazo[4,5-c][l,5]naphthyridin-4-amine (0.600 g, 1.51
mmol), the boronic acid indicated in the following table (1.82 mmol), potassium carbonate
(0.691 g, 5.00 mmol), dichlorobis(triphenylphosphine)palladium(H) (0.011 g, 0.015
mmol), DME (7 mL), and water (3 mL) was stirred in a pressure vessel. The vessel was
30 sealed, and the suspension was heated at 1 10 °C for the time indicated in the following
table, allowed to cool to room temperature, and concentrated under reduced pressure. The
residue was dissolved in methanol and dichloromethane. Silica gel was added, and the
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mixture was concentrated under reduced pressure. The residue was purified by automated
flash chromatography (FLASH 40+M cartridge, eluting with methanol in ethyl acetate
with the percentage of methanol given in the table). Acetonitrile was added to the purified
product to form a solid, which was isolated by filtration, washed with acetonitrile, and
5 dried in a vacuum oven at 65 °C or 80 °C to provide the products with the structures
indicated in the table. Analytical data is provided below the table.
Examples 339- 342
MH 2
R XTy
Example
Boronic acid
Reaction Time
Methanol in
eluent
R 3
339
Phenylboronic acid
64 hours
3% to 10%
a
340
(3-Methylsulfonylamino-
phenyl)boronic acid
14.5 hours
3% to 12%
o CH 3
341
3-(Morpholine-4-carbonyl)-
phenylboronic acid
16 hours
5% to 15%
€ {
342
6-Fluoropyridine-3 -boronic
acid
16 hours
3% to 10%
Example 339: 2-(Ethoxymethyl)-l-(2-flu.oro-2-methylpropyl)-7-phenyl-l^-imidazo[4,5-
10 c][l,5]naphthyridin-4-amine (150 mg) was obtained as a white solid, mp 173-174 °C.
Anal. Calcd for C22H24FN5O: C, 67.16; H, 6.15; N, 17.80. Found: C, 67.09; H, 6.31; N,
17.71.
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Example 340: A^{3^4-Amino-2-(ethoxymethyl)-l-(2-fliioro-2-methylpropyl)-li^-
imidazo[4,5-c][l,5]naphthyridin-7-yl]phenyl}methanesalfonamide (126 mg) was obtained
as a white solid, mp 208-209 °C.
Anal. Calcd for C23H27FN6O3S: C, 56.78; H, 5.59; N, 17.27. Found: C, 56.67; H, 5.41; N,
5 17.23.
Example 341 : 2-(Ethoxymethyl)-l-(2-fluoro-2-methylpropyl)-7-[3-(morpholin-4-
ylcarbonyl)phenyl]-17/-imidazo[4,5-c][l,5]naphthyridin-4-amine (192 mg) was obtained
as a white solid, mp 167-168 °C.
Anal. Calcd for C27H31FN6O3: C, 64.02; H, 6.17; N, 16.59. Found: C, 63.80; H, 6.01; N,
10 16.67.
Example 342: 2-(Ethoxymethyl)-l-(2-fluoro-2-methylpropyl)-7-(6-fluoropyridin-3-yl)-
l//-imidazo[4,5-c][l,5]naphthyridin-4-amine (177 mg) was obtained as a white solid, mp
198-199 °C.
Anal. Calcd for C 2 iH 22 F 2 N 6 0: C, 61.16; H, 5.38; N, 20.38. Found: C, 60.95; H, 5.17; N,
15 20.48.
Examples 343-350
The methods described in Examples 154- 194 •were followed using 7-bromo-2-
(ethoxymethyl)-l -(2-fluoro-2-methylpropyl)- l#-imidazo[4,5-c] [ 1 ,5]naphthyridin-4-amine
20 (40.0 mg, 0. 100 mmol) instead of l-(4-amino-7-bromo-2-ethyl-l#-imidazo[4,5-
c][l,5]naphthyridin-l-yl)-2-methylpropan-2-ol with the modification that the samples
were not diluted in methanol after the initial heating at 8 0 °C overnight. The table below
shows the reagent added to each test tube, the structure of the resulting compound, and the
observed accurate mass for the isolated trifluoroacetate salt.
154
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